AU2018352245B2

AU2018352245B2 - Compositions and methods for treating cancer with anti-CD22 immunotherapy

Info

Publication number: AU2018352245B2
Application number: AU2018352245A
Authority: AU
Inventors: Dimiter S. Dimitrov; Boro Dropulic; Rimas J. ORENTAS; Dina SCHNEIDER; Zhongyu Zhu
Original assignee: USA As Represented By Secretary; Lentigen Technology Inc
Current assignee: Lentigen Technology Inc; US Department of Health and Human Services
Priority date: 2017-10-16
Filing date: 2018-10-16
Publication date: 2025-07-03
Anticipated expiration: 2038-10-16
Also published as: ES2958849T3; JP7275118B2; EP3697426A4; CN111629735B; CN111629735A; WO2019079249A9; EP3697426B1; JP2023106442A; CN118345102A; US11878052B2; JP2025138681A; CA3078962A1; EP4279584A2; US20240108706A1; AU2025230694A1; AU2018352245A1; EP3697426A1; EP3697426C0; JP7696393B2; JP2021500881A

Abstract

Chimeric antigen receptors (CARs) containing CD22 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the CARsare also disclosed. Methods of treating or preventing cancer in a subject, and methods of making CAR T cells are also disclosed.

Description

WO wo 2019/079249 PCT/US2018/056011

COMPOSITIONS AND METHODS FOR TREATING CANCER WITH ANTI- CD22 IMMUNOTHERAPY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. Section 119(e) to U.S.

Provisional Patent Application No. 62/572,926 filed on October 16, 2017, the entire contents of

which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII

copy, created on October 12, 2018, is named Sequence Listing. txt and and is 234 is 234 kilobytes kilobytes in size. in size.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was created in the performance of a Cooperative Research and

Development Agreement with the National Institutes of Health, an Agency of the Department of

Health and Human Services. The Government of the United States has certain rights in this

invention.

FIELD OF THE DISCLOSURE

This application relates to the field of cancer, particularly to CD22 antigen binding

domains and chimeric antigen receptors (CARs) containing such CD22 antigen binding domains

and methods of use thereof.

BACKGROUND

Cancer is one of the most deadly threats to human health. In the U.S. alone, cancer affects

nearly 1.3 million new patients each year, and is the second leading cause of death after

cardiovascular disease, accounting for approximately 1 in 4 deaths. Solid tumors are responsible

for most of those deaths. Although there have been significant advances in the medical treatment

WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

of certain cancers, the overall 5-year survival rate for all cancers has improved only by about 10%

in the past 20 years. Cancers, or malignant tumors, metastasize and grow rapidly in an

uncontrolled manner, making treatment extremely difficult.

The present standard of care for B-lineage leukemias may consists of remission induction

treatment by high dose of chemotherapy or radiation, followed by consolidation, and may feature

stem cell transplantation and additional courses of chemotherapy as needed (see the world wide

web at cancer.gov). High toxicity associated with these treatments, as well as the risk of

complications, such as relapse, secondary malignancy, or graft versus host disease (GVHD),

motivate the search for better therapeutic alternatives. CD22, also known as SIGLEC-2 (sialic

acid-binding immunoglobulin-likelectin-2), is 95 kDa transmembrane surface glycoprotein and

contains contains 66 Ig-like Ig-like C2-type C2-type domains domains and and one one Ig-like Ig-like V-type V-type domain domain (uniprot.org/uniprot/P20273#structure, (uniprot.org/uniprot/P20273#structure, accessed accessed 07/12/2017). 07/12/2017). During During B-cell B-cell ontogeny, ontogeny, CD22 CD22 is is

expressed on the B-cell surface starting at the pre-B cell stage, persists on mature B cells and is

lost on plasma cells (Nitschke L, 2009, Immunological Reviews, 230:128-143). CD22 contains

intracellular ITIM (immuoreceptor tyrosine-based inhibition motifs) domains which following the

engagement of the B cell receptor for antigen serve to down-modulate cellular activation.

Antibody binding of CD22 induces co-localization with SHP-1, and intracellular phosphatase that

also serves to down-modulate phosorylation-based signal transduction (Lumb S, Fleishcer SJ,

Wiedemann A, Daridon C, Maloney A, Shock A, Dorner T, 2016, Journal of Cell Communication

and Signaling, 10:143-151). The key point of relevance for treatment of B cell malignancies is

that CD22 is expressed in a tightly regulated manner on normal B cells, but not expressed on

hematopoietic stem cells, or mature plasma cells, making it a suitable target antigen for B cell

leukemias. The expression of CD22 on both adult and pediatric (pre-B-ALL) B cell malignancies

has led to exploiting this target for both antibody and chimeric antigen receptor (CAR)-T cell-

based therapy (Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, Dimitrov

DS, Morgan RA, FitzGerlad DJ, Barrett DM, Wayne AS, Mackall CL, Orentas RJ, 2013, Blood,

121:1165-1174) (Wayne AS, Kreitman RJ, Findley HW, Lew G, Delbrook C, Steinberg SM,

Stetler-Stevenson M, FitzGerald DJ, Pastan I, 2010, Clinical Cancer Research, 16:1894-1903).

A number of novel approaches to treat B cell leukemia and lymphoma have been developed, including anti-CD22 antibodies linked to bacterial toxins or chemotherapeutic agents

(Wayne AS, FitzGerald DJ, Kreitman RJ, Pastan I, 2014, Immunotoxins for leukemia, Blood,

123:2470-2477). Inotuzumab Ozogamicin (CMC-544, a humanized version of the murine

monoclonal antibody G5/44) is an antibody drug conjugate and is currently being evaluated in

clinical trials, either as a single agent or given in combination with chemotherapy (NCT01664910,

WO wo 2019/079249 PCT/US2018/056011

sponsor: M.D.Anderson sponsor: M.D. Anderson Cancer Cancer Center) Center) (DiJoseph (DiJoseph JF, et JF, al., et al., 2004, 2004, Blood, Blood, 103:1807-1814). 103:1807-1814). As a As a

single agent, outcomes exceeded those seen with standard therapy, although significant liver

toxicity was noted (Kantarjian H, et al., 2016, Inotuzumb ozogamicin versus standard therapy for

acute lymphoblastic leukemia (ALL), New England Journal of Medicine, 375:740-753).

Unmodified CD222 therapeutic antibody, CD22 therapeutic antibody, Epratuzumab, Epratuzumab, is is also also being being tested tested in in combination combination with with

chemotherapy (NCT01219816, sponsor: Nantes University Hospital). Epratuzumab is a chimeric

protein composed of murine CDRs grafted onto a human antibody framework. Although effective

in some leukemias, Moxetumomab pasudotox in not in broad clinical development due to

problems with both immunogenicity of the bacterial toxin to which the antibody is fused and

modest or comparable levels of activity with other agents (see NCT01829711, sponsor:

MedImmune, LLC). To date, many of the binding moieties for CD22 employed in CAR constructs utilize a domain derived from these murine antibodies and do not effectively activate T

cells that target this CD222 domain (such CD22 domain (such as as the the HA22 HA22 anti-CD22 anti-CD22 binder binder used used as as the the basis basis for for

Moxetumomab pasudotox, see James SE, Greenberg PD, Jensen MC, Lin Y, Wang J, Till BG,

Raubitschek AA, Forman SJ, Press OW, 2008, Jounral of Immunology 180:7028-7038). One

anti-CD22 anti-CD22 binder binder that that is is effective effective as as an an anti-CD22 anti-CD22 CAR CAR is is currently currently in in clinical clinical trial trial at at the the

National Institutes of Health (NIH), although results have not been published (ClinicalTrials.gov

Identifier: NCT02315612, Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults

with Recurrent or Refractory CD22-expressing B Cell Malignancies, sponsor: NCI). This binder

is based on the m971 fully human antibody developed in the laboratory of one of the inventors in

this application, Dr. Dimiter Dimitrov (Xiao X, Ho M, Zhu Z, Pastan I, Dimitrov D, 2009,

Identification and characterization of fully human anti-CD22 monoclonal antibodies, MABS,

1:297-303). The m971 domain was proven effective as a CAR in work supervised by another of

the inventors in this application, Dr. Rimas Orentas (Haso W, et al., 2013, Anti-CD22-CARs

targeting B-cell precursor ALL, Blood, 121:1165-1174).

Chimeric Antigen Receptors (CARs) are hybrid molecules comprising three essential

units: (1) an extracellular antigen-binding motif, (2) linking/transmembrane motifs, and (3)

intracellular T-cell signaling motifs (Long AH, Haso WM, Orentas RJ. Lessons learned from a

highly-active CD22-specific CAR. Oncoimmunology. 2013; 2 (4):e23621). The antigen-binding

motif of a CAR is commonly fashioned after a single chain Fragment variable (ScFv), the the

minimal binding domain of an immunoglobulin (Ig) molecule. Alternate antigen-binding motifs,

such as receptor ligands (i.e., IL-13 been engineered has been to bind engineered tumor to bind expressed tumor IL-13 expressed receptor), IL-13 receptor),

intact immune receptors, library-derived peptides, and innate immune system effector molecules

(such as NKG2D) also have been engineered into CARs. Alternate cell targets for CAR

WO wo 2019/079249 PCT/US2018/056011

expression (such as NK or gamma-delta T cells) are also under development (Brown CE et al Clin

Cancer Res. 2012;18(8):2199-209; Lehner M et al. PLoS One. 2012; 7 (2):e31210). There

remains significant work to be done with regard to defining the most active T-cell population to

transduce with CAR vectors, determining the optimal culture and expansion techniques, and

defining the molecular details of the CAR protein structure itself.

The linking motifs of a CAR can be a relatively stable structural domain, such as the

constant domain of IgG, or designed to be an extended flexible linker. Structural motifs, such as

those derived from IgG constant domains, can be used to extend the ScFv binding domain away

from the T-cell plasma membrane surface. This may be important for some tumor targets where

the binding domain is particularly close to the tumor cell surface membrane (such as for the

disialoganglioside GD2; Orentas et al., unpublished observations). To date, the signaling motifs

used in CARs always include the CD3-5 CD3-Ç chain because this core motif is the key signal for T cell

activation. The first reported second-generation CARs featured CD28 signaling domains and the

CD28 transmembrane sequence. This motif was used in third-generation CARs containing

CD137 (4-1BB) signaling motifs as well (Zhao Y et al J Immunol. 2009; 183 (9): 5563-74). With

the advent of new technology, the activation of T cells with beads linked to anti-CD3 and anti-

CD28 antibody, and the presence of the canonical "signal 2" from CD28 was no longer required

to be encoded by the CAR itself. Using bead activation, third-generation vectors were found to be

not superior to second-generation vectors in in vitro assays, and they provided no clear benefit

over second-generation vectors in mouse models of leukemia (Haso W, Lee DW, Shah NN,

Stetler-Stevenson Stetler-Stevenson M, M, Yuan Yuan CM, CM, Pastan Pastan IH, IH, Dimitrov Dimitrov DS, DS, Morgan Morgan RA, RA, FitzGerald FitzGerald DJ, DJ, Barrett Barrett

DM, Wayne AS, Mackall CL, Orentas RJ. Anti-CD22-CARs targeting B cell precursor ALL,

Blood. 2013; 121 (7):1165-74; Kochenderfer JN et al. Blood. 2012; 119 (12):2709-20). In

addition to CD137, other tumor necrosis factor receptor superfamily members such as OX40 also

are able to provide important persistence signals in CAR-transduced T cells (Yvon E et al. Clin

Cancer Res. 2009;15(18):5852-60). Equally important are the culture conditions under which the

CAR T-cell populations were cultured, for example the inclusion of the cytokines IL-2, IL-7,

and/or IL-15 (Kaiser AD et al. Cancer Gene Ther. 2015; 22(2):72-78.

Current challenges in the more widespread and effective adaptation of CAR therapy for

cancer relate to a paucity of compelling targets. Creating binders to cell surface antigens is now

readily achievable, but discovering a cell surface antigen that is specific for tumor while sparing

normal tissues remains a formidable challenge. One potential way to imbue greater target cell

specificity to CAR-expressing T cells is to use combinatorial CAR approaches. In one system, the

CD3-5 CD3-Ç and CD28 signal units are split between two different CAR constructs expressed in the

WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

same cell; in another, two CARs are expressed in the same T cell, but one has a lower affinity and

thus requires the alternate CAR to be engaged first for full activity of the second (Lanitis E et al.

Cancer Immunol Res. 2013;1(1):43-53; Kloss CC et al. Nat Biotechnol. 2013;31(1):71-5). A

second challenge for the generation of a single ScFv-based CAR as an immunotherapeutic agent

is tumor cell heterogeneity. At least one group has developed a CAR strategy for glioblastoma

whereby the effector cell population targets multiple antigens (HER2, IL-13Ra, EphA2) at the

same time in the hope of avoiding the outgrowth of target antigen-negative populations. (Hegde M

et al. Mol Ther. 2013;21(11):2087-101).

T-cell-based immunotherapy has become a new frontier in synthetic biology; multiple

promoters and gene products are envisioned to steer these highly potent cells to the tumor

microenvironment, where T cells can both evade negative regulatory signals and mediate effective

tumor killing. The elimination of unwanted T cells through the drug-induced dimerization of

inducible caspase 9 constructs with chemical-based dimerizers, such as AP1903, demonstrates one

way in which a powerful switch that can control T-cell populations can be initiated

pharmacologically (Di Stasi A et al. N Engl J Med. 2011;365(18):1673-83) 2011;365(18):1673-83).The Thecreation creationof of

effector T-cell populations that are immune to the negative regulatory effects of transforming

growth factor-ß factor-B by the expression of a decoy receptor further demonstrates the degree to which

effector T cells can be engineered for optimal antitumor activity (Foster AE et al. J Immunother.

2008;31(5):500-5). Thus, 2008;31(5):500-5). while Thus, it appears while that CARs it appears thatcan trigger CARs T-cell activation can trigger in a manner in a manner T-cell activation

similar to an endogenous T-cell receptor, a major impediment to the clinical application of this

technology to date has been limited in vivo expansion of CAR+ T cells, rapid disappearance of the

cells after infusion, and disappointing clinical activity. This may be due in part to the murine

origin of some of the CAR sequences employed, an obstacle directly addressed by our inventions

disclosed herein.

Accordingly, there is an urgent and long felt need in the art for discovering novel

compositions and methods for treatment of B-ALL, DLBCL, FL, and other CD22-expressing B

cell malignancies using an approach that can exhibit specific and efficacious anti-tumor effect

without the aforementioned short comings.

The present invention addresses these needs by providing CAR compositions and

therapeutic methods that can be used to treat cancers and other diseases and/or conditions. In

particular, the present invention as disclosed and described herein provides CARs that may be

used for the treatment of diseases, disorders or conditions associated with dysregulated expression

of CD22 and which CARs contain CD22 antigen binding domains that exhibit a high surface expression on transduced transducedTTcells, cells, exhibit exhibit aa high high degree degree of of cytolysis cytolysis of of CD22-expressing cells, and and 03 Mar 2025 2018352245 03 Mar 2025 expression on CD22-expressing cells, in in which the transduced which the transduced TTcells cells demonstrate in vivo demonstrate in vivo expansion andpersistence. expansion and persistence. It is to be understood that if any prior art publication is referred to herein, such reference It is to be understood that if any prior art publication is referred to herein, such reference does notconstitute does not constituteananadmission admission thatthat the the publication publication formsforms a parta ofpart the of the general common common general knowledge in the art in Australia or any other country. knowledge in the art in Australia or any other country.

SUMMARY 2018352245

SUMMARY Novelanti-CD22 Novel anti-CD22 antibodies antibodies or antigen or antigen binding binding domains domains thereofthereof and chimeric and chimeric antigen antigen receptors (CARs) receptors thatcontain (CARs) that containsuch suchCD22 CD22 antigen antigen binding binding domains domains are provided are provided herein, herein, as well as well as as host cells host cells (e.g., (e.g., T cells) expressing T cells) expressingthe thereceptors, receptors,andand nucleic nucleic acidacid molecules molecules encoding encoding the the receptors. The receptors. TheCARs CARs exhibit exhibit a high a high surface surface expression expression on on transduced transduced T cells, T cells, withwith a high a high degree degree

of of cytolysis, cytolysis, and and with with transduced transduced TTcell cell expansion expansionand andpersistence persistenceininvivo. vivo.Methods Methodsof of using using thethe

disclosed CARs,host disclosed CARs, hostcells, cells, and andnucleic nucleicacid acidmolecules moleculesarearealso alsoprovided, provided,forforexample, example, to to treata a treat

cancer in a subject. cancer in a subject.

Thus, in Thus, in one aspect, an one aspect, an isolated isolated polynucleotide polynucleotide encoding encoding aa human humananti-CD22 anti-CD22 antibody antibody or aor a fragment thereof is fragment thereof is provided provided comprising a nucleic comprising a nucleic acid acid sequence sequence selected selected from the group from the group consisting of SEQ ID NOs: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, consisting of SEQ ID NOs: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161,

and 171. and 171. In one In one embodiment, embodiment,ananisolated isolatedpolynucleotide polynucleotide encoding encodinga afully fullyhuman human anti-CD22 anti-CD22

antibody or antibody or aa fragment fragmentthereof thereofis is provided, provided, wherein whereinthe theantibody antibodyorora afragment fragmentthereof thereofcomprises comprises aa fragment fragmentselected selectedfrom fromthethegroup group consisting consisting of Fab of an an Fab fragment, fragment, an F(ab') an F(ab') 2 fragment, fragment, an Fv an Fv

fragment, and aa single fragment, and single chain chain Fv (ScFv). Fv (ScFv).

In one In one embodiment, embodiment,ananisolated isolatedpolynucleotide polynucleotide encoding encodinga afully fullyhuman human anti-CD22 anti-CD22

antibody or antibody or aa fragment fragmentthereof thereofis is provided, provided, wherein whereinthe theantibody antibodyorora afragment fragmentthereof thereofcomprises comprises an aminoacid an amino acidsequence sequenceselected selectedfrom from thegroup the group consisting consisting of of SEQ SEQ ID NOs: ID NOs: 2, 22, 2, 12, 12, 32, 22, 32, 42, 42, 52, 52,

62, 72, 82, 62, 72, 82,92, 92,102, 102,112, 112, 122, 122, 132,132, 142,142, 152, 152, 162,172. 162, and and 172. In one In aspect, an one aspect, isolated nucleic an isolated nucleic acid acid molecule encodinga aCAR molecule encoding CAR is provided is provided comprising, comprising,

from N-terminus from N-terminus toto C-terminus, C-terminus, at at least least one CD22antigen one CD22 antigenbinding bindingdomain domain encoded encoded by aby a nucleotide sequence nucleotide sequencecomprising comprising a nucleic a nucleic acidacid sequence sequence selected selected from from the group the group consisting consisting of of SEQ SEQ IDID NOs: NOs: 1, 1, 11,11, 21,21, 31,31, 41,41,51,51,61,61,71, 71,81, 81,91, 91,101, 101,111, 111,121, 121,131, 131,141, 141,151, 151,161161 andand 171, 171, at at

least one transmembrane least one transmembrane domain, domain, andleast and at at one leastintracellular one intracellular signaling signaling domain.domain.

66

21537896_1(GHMatters) 21537896_1 (GHMatters)P113421.AU P113421.AU 03/03/2025 03/03/2025

WO wo 2019/079249 PCT/US2018/056011

In one embodiment, an isolated nucleic acid molecule encoding the CAR is provided

wherein the encoded extracellular CD22 antigen binding domain comprises at least one single

chain variable fragment of an antibody that binds to CD22.

In another embodiment, an isolated nucleic acid molecule encoding the CAR is provided

wherein the encoded extracellular CD22 antigen binding domain comprises at least one heavy

chain variable region of an antibody that binds to CD22.

In yet another embodiment, an isolated nucleic acid molecule encoding the CAR is

provided wherein the encoded CAR extracellular CD22 antigen binding domain further comprises

at least one lipocalin-based antigen binding antigen (anticalins) that binds to CD22.

In one embodiment, an isolated nucleic acid molecule is provided wherein the encoded

extracellular CD222 antigen binding CD22 antigen binding domain domain is is connected connected to to the the transmembrane transmembrane domain domain by by aa linker linker

domain.

wherein the encoded CD22 extracellular antigen binding domain is preceded by a sequence

encoding a leader or signal peptide.

provided providedcomprising comprisingat at least one CD22 least antigen one CD22 bindingbinding antigen domain encoded domain by a nucleotide encoded sequence by a nucleotide sequence

comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1, 11, 21,

31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, and 171 and wherein the CAR

additionally encodes an extracellular antigen binding domain targets an antigen that includes, but

is not limited to, CD20, CD22, ROR1, mesothelin, CD33, CD38, CD123 (IL3RA), CD138,

BCMA (CD269), GPC2, GPC3, FGFR4, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2,

TSLPR, NY-ESO-1 TCR, MAGE A3 TCR, or any combination thereof.

In certain embodiments, an isolated nucleic acid molecule encoding the CAR is provided

wherein the additionally encoded extracellular antigen binding domain comprises an anti-CD19

ScFv antigen binding domain, an anti-CD20 ScFv antigen binding domain, an anti-ROR1 ScFv

antigen binding domain, an anti-mesothelin ScFv antigen binding domain, an anti-CD33 ScFv

antigen binding domain, an anti-CD38 ScFv antigen binding domain, an anti-CD123 (IL3RA)

ScFv antigen binding domain, an anti-CD138 ScFv antigen binding domain, an anti-BCMA

(CD269) ScFv antigen binding domain, an anti-GPC2 ScFv antigen binding domain, an anti-

GPC3 ScFv antigen binding domain, an anti-FGFR4 ScFv antigen binding domain, an anti-

TSLPR ScFv antigen binding domain an anti-c-Met ScFv antigen binding domain, an anti-PMSA

ScFv antigen binding domain, an anti-glycolipid F77 ScFv antigen binding domain, an anti-

EGFRVIII EGFRvIII ScFv antigen binding domain, an anti-GD-2 ScFv antigen binding domain, an anti-NY-

ESO-1 TCR ScFv antigen binding domain, an anti-MAGE A3 TCR ScFv antigen binding domain,

or an amino acid sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof, or any

combination thereof.

In one aspect, the CARs provided herein further comprise a linker or spacer domain.

wherein the extracellular CD22 antigen binding domain, the intracellular signaling domain, or

both are connected to the transmembrane domain by a linker or spacer domain.

wherein the encoded linker domain is derived from the extracellular domain of CD8 or CD28, and

is linked to a transmembrane domain.

wherein the encoded CAR further comprises a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta

chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22,

CD33, CD37, CD64, CD80, CD83, CD86, CD134, CD137, CD154, TNFRSF19, or a combination

thereof.

provided wherein the encoded intracellular signaling domain further comprises a CD3 zeta

intracellular domain.

wherein the encoded at least one intracellular signaling domain comprises a costimulatory

domain, a primary signaling domain, or a combination thereof.

In further embodiments, an isolated nucleic acid molecule encoding the CAR is provided

wherein the encoded at least one costimulatory domain comprises a functional signaling domain

of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10,

DAP12, and 4-1BB (CD137), or a combination thereof.

In one embodiment, an isolated nucleic acid molecule encoding the CAR is provided that

further contains a leader sequence or signal peptide wherein the leader or signal peptide

nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 190.

provided wherein the encoded leader sequence comprises the amino acid sequence of SEQ ID ID

NO: 191.

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In one aspect, a CAR is provided herein comprising, from N-terminus to C-terminus, at

least one CD22 antigen binding domain, at least one transmembrane domain, and at least one

intracellular signaling domain.

In one embodiment, a CAR is provided wherein the extracellular CD22 antigen binding

domain comprises at least one single chain variable fragment of an antibody that binds to the

antigen, or at least one heavy chain variable region of an antibody that binds to the antigen, or a

combination thereof.

In another embodiment, a CAR is provided wherein the at least one transmembrane

domain comprises a transmembrane domain of a protein selected from the group consisting of the

alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8,

CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, TNFRSF19, or a combination thereof.

In some embodiments, the CAR is provided wherein CAR additionally encodes an

extracellular antigen binding domain comprising CD19, CD20, RORI, ROR1, mesothelin, CD33, CD38,

CD123 (IL3RA), CD138, BCMA (CD269), GPC2, GPC3, FGFR4, TSLPR, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, TSLPR, NY-ESO-1 TCR, MAGE A3 TCR, or an amino acid

sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof, or any combination

thereof.

In one embodiment, the CAR is provided wherein the extracellular antigen binding domain

comprises an anti-CD19 ScFv antigen binding domain, an anti-CD20 ScFv antigen binding

domain, an anti-RORI anti-ROR1 ScFv antigen binding domain, an anti-mesothelin ScFv antigen binding

domain, an anti-CD33 ScFv antigen binding domain, an anti-CD38 ScFv antigen binding domain,

an anti-CD123 (IL3RA) ScFv antigen binding domain, an anti-CD138 ScFv antigen binding

domain, an anti-BCMA (CD269) ScFv antigen binding domain, an anti-GPC2 ScFv antigen

binding domain, an anti-GPC3 ScFv antigen binding domain, an anti-FGFR4 ScFv antigen

binding domain, anti-TSLPR ScFv antigen binding domain, an anti-c-Met ScFv antigen binding

domain, an anti-PMSA ScFv antigen binding domain, an anti-glycolipid F77 ScFv antigen

binding domain, an anti-EGFRvIII ScFv antigen binding domain, an anti-GD-2 ScFv antigen

binding domain, an anti-NY-ESO-1 TCR ScFv antigen binding domain, an anti-MAGE A3 TCR

ScFv antigen binding domain, or an amino acid sequence with 85%, 90%, 95%, 96%, 97%, 98%

or 99% identity thereof, or any combination thereof.

In another embodiment, a CAR is provided wherein the at least one intracellular signaling

domain comprises a costimulatory domain and a primary signaling domain.

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In yet another embodiment, a CAR is provided wherein the at least one intracellular

signaling domain comprises a costimulatory domain comprising a functional signaling domain of

a protein selected from the group consisting of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-

1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, and 4-1BB (CD137), or a combination thereof.

In one embodiment, the nucleic acid sequence encoding a CAR comprises the nucleic acid

sequence of SEQ ID NO: 3 (LTG 2202 LP-16P-CD8 TM-41BB-CD3zeta CAR nucleic acid

sequence (FIGURE 2A)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 4 (LTG 2202 LP-16P-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2A)).

In another embodiment, the nucleic acid sequence encoding a CAR comprises the nucleic

acid sequence of SEQ ID NO: 13 (LTG 2246 LP-24P-CD8 TM-41BB-CD3zeta CAR nucleic acid

sequence (FIGURE 2B)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 14 (LTG 2246 LP-24P-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2B)).

acid sequence of SEQ ID NO: 23 (LTG 2247 LP-25P-CD8 TM-41BB-CD3zeta CAR nucleotide

sequence (FIGURE 2C)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 24 (LTG 2247 LP-25P-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2C)).

acid sequence of SEQ ID NO: 33 (LTG 2248 LP-11S-CD8 TM-41BB-CD3zeta CAR nucleic acid

sequence (FIGURE 2D)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 34 (LTG 2248 LP-11S-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2D)).

acid sequence of SEQ ID NO: 43 (LTG 2249 LP-12S-CD8 TM-41BB-CD3zeta CAR nucleic acid

sequence (FIGURE 2E)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 28 LTG 2208 LP-12S-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2E)).

acid sequence of SEQ ID NO: 53 (LTG 2203 LP-16P3-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2F)). In one embodiment, the nucleic acid sequence encodes a CAR wo 2019/079249 WO PCT/US2018/056011 comprising the amino acid sequence of SEQ ID NO: 54 (LTG 2203 LP-16P3-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2F)).

acid sequence of SEQ ID NO: 63 (LTG 2204 LP-16P16-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2G)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 34 (LTG 2204 LP-16P16-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2G)).

acid sequence of SEQ ID NO: 73 (LTG 2205 LP-16P20-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2H)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 74 (LTG 2205 LP-16P20-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2H)).

acid sequence of SEQ ID NO: 83 (LTG 2206 LP-16P2-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2I)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 84 (LTG 2206 LP-16P2-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2I)).

acid sequence of SEQ ID NO: 93 (LTG 2207 LP-16P6-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2J)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 94 (LTG 2205 LP-16P20-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2J)).

acid sequence of SEQ ID NO: 103 (LTG 2208 LP-16P10-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2K)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 104 (LTG 2208 LP-16P10-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2K)).

acid sequence of SEQ ID NO: 113 (LTG 2209 LP-16P17-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2L)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 114 (LTG 2209 LP-16P17-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2L)).

acid sequence of SEQ ID NO: 123 (LTG 2210 LP-16P20v2-CD8 TM-41BB-CD3zeta CAR

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nucleic acid sequence (FIGURE 2M)). In one embodiment, the nucleic acid sequence encodes a

CAR comprising the amino acid sequence of SEQ ID NO: 124 (LTG 2210 LP-16P20v2-CD8

TM-41BB-CD3zeta CAR amino acid sequence (FIGURE 2M)).

acid sequence of SEQ ID NO: 133 (LTG 2216 LP-16P1-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2N)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 134 (LTG 2216 LP-16P1-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2H)).

acid sequence of SEQ ID NO: 143 (LTG 2217 LP-16P3v2-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 20)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 144 (LTG 2217 LP-16P3v2-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 20)).

acid sequence of SEQ ID NO: 153 (LTG 2218 LP-16P8-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2P)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 154 (LTG 2218 LP-16P8-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2P)).

acid sequence of SEQ ID NO: 163 (LTG 2219 LP-16P13-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2Q)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 164 (LTG 2219 LP-16P13-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2Q)).

acid sequence of SEQ ID NO: 173 (LTG 2220 LP-16P15-CD8 TM-41BB-CD3zeta CAR nucleic

acid sequence (FIGURE 2R)). In one embodiment, the nucleic acid sequence encodes a CAR

comprising the amino acid sequence of SEQ ID NO: 174 (LTG 2220 LP-16P15-CD8 TM-41BB-

CD3zeta CAR amino acid sequence (FIGURE 2R)).

In one aspect, the CARs disclosed herein are modified to express or contain a detectable

marker for use in diagnosis, monitoring, and/or predicting the treatment outcome such as as

progression free survival of cancer patients or for monitoring the progress of such treatment.

In one embodiment, the nucleic acid molecule encoding the disclosed CARs can be

contained in a vector, such as a viral vector vector.The Thevector vectoris isa aDNA DNAvector, vector,an anRNA RNAvector, vector,a a

WO wo 2019/079249 PCT/US2018/056011

plasmid vector, a cosmid vector, a herpes virus vector, a measles virus vector, a lentivirus vector,

adenoviral vector, or a retrovirus vector, or a combination thereof.

In certain embodiments, the vector further comprises a promoter wherein the promoter is

an inducible promoter, a tissue specific promoter, a constitutive promoter, a suicide promoter or

any combination thereof.

In yet another embodiment, the vector expressing the CAR can be further modified to

include one or more operative elements to control the expression of CAR T cells, or to eliminate

CAR-T cells by virtue of a suicide switch. The suicide switch can include, for example, an

apoptosis inducing signaling cascade or a drug that induces cell death. In a preferred

embodiment, the vector expressing the CAR can be further modified to express an enzyme such

thymidine kinase (TK) or cytosine deaminase (CD).

In another aspect, host cells including the nucleic acid molecule encoding the CAR are

also provided. In some embodiments, the host cell is a T cell, such as a primary T cell obtained

from a subject. In one embodiment, the host cell is a CD8+ T cell.

In yet another aspect, a pharmaceutical composition is provided comprising an anti-tumor

effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid

sequence that encodes a CAR, wherein the CAR comprises at least one extracellular antigen

binding domain comprising a CD22 antigen binding domain comprising the amino acid sequence

of SEQ ID NO. 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, or 172, at

least one linker domain, at least one transmembrane domain, and at least one intracellular

signaling domain, wherein the T cells are T cells of a human having a cancer. The cancer

includes, inter alia, a hematological cancer such as leukemia (e.g., (CLL, ALL, AML or CML,

lymphoma (e.g., mantle cell lymphoma, non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma) or multiple myeloma, or a combination thereof.

In one embodiment, a pharmaceutical composition is provided wherein the at least one

transmembrane domain of the CAR contains a transmembrane domain of a protein selected from

the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon,

CD45, CD4, CD5, CD8, CD9, CD16, CD22, Mesothelin, CD33, CD37, CD64, CD80, CD83,

CD86, CD134, CD137, CD154, TNFRSF19, or a combination thereof.

In another embodiment, a pharmaceutical composition is provided wherein the human

cancer includes an adult carcinoma comprising coral and pharynx cancer (tongue, mouth,

pharynx, head and neck), digestive system cancers (esophagus, stomach, small intestine, colon,

rectum, anus, liver, interhepatic bile duct, gallbladder, pancreas), respiratory system cancers

(larynx, lung and bronchus), bones and joint cancers, soft tissue cancers, skin cancers (melanoma,

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basal and squamous cell carcinoma), pediatric tumors (neuroblastoma, rhabdomyosarcoma rhabdomyosarcoma,

osteosarcoma, Ewing's sarcoma), tumors of the central nervous system (brain, astrocytoma,

glioblastoma, glioma), and cancers of the breast, the genital system (uterine cervix, uterine corpus,

ovary, vulva, vagina, prostate, testis, penis, endometrium), the urinary system (urinary bladder,

kidney and renal pelvis, ureter), the eye and orbit, the endocrine system (thyroid), and the brain

and other nervous system, or any combination thereof.

In yet another embodiment, a pharmaceutical composition is provided comprising an anti-

tumor effective amount of a population of human T cells of a human having a cancer wherein the

cancer is a refractory cancer non-responsive to one or more chemotherapeutic agents. The cancer

includes hematopoietic cancer, myelodysplastic syndrome pancreatic cancer, head and neck

cancer, cutaneous tumors, minimal residual disease (MRD) in ALL, AML, adult B cell

malignancies including, CLL , CML, NHL, pediatric B cell malignancies (including B lineage

ALL), multiple myeloma lung cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer,

melanoma or other hematological cancer and solid tumors, or any combination thereof.

In another aspect, methods of making CAR-containing T cells (hereinafter "CAR-T cells")

are provided. The methods include transducing a T cell with a vector or nucleic acid molecule

encoding a disclosed CAR that specifically binds CD22, thereby making the CAR-T cell.

In yet another aspect, a method of generating a population of RNA-engineered cells is

provided that comprises introducing an in vitro transcribed RNA or synthetic RNA of a nucleic

acid molecule encoding a disclosed CAR into a cell of a subject, thereby generating a CAR cell.

In yet another aspect, a method for diagnosing a disease, disorder or condition associated

with the expression of CD22 on a cell, is provided comprising a) contacting the cell with a human

anti-CD19 antibody or fragment thereof, wherein the antibody or a fragment thereof comprises an

amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62,

72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172; and b) detecting the presence of CD22 wherein

the presence of CD19 diagnoses for the disease, disorder or condition associated with the

expression of CD22.

In one embodiment, the disease, disorder or condition associated with the expression of

CD22 is cancer including hematopoietic cancer, myelodysplastic syndrome pancreatic cancer,

head and neck cancer, cutaneous tumors, minimal residual disease (MRD) in ALL, AML, adult B

cell malignancies including, CLL, CML, NHL, pediatric B cell malignancies (including B lineage

PCT/US2018/056011

In another embodiment, a method of diagnosing, prognosing, or determining risk of a

CD19-related disease in a mammal, is provided comprising detecting the expression of CD22 in a

sample derived from the mammal comprising: a) contacting the sample with a human anti-CD22

antibody or fragment thereof, wherein the antibody or a fragment thereof comprises an amino acid

sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92,

102, 112, 122, 132, 142, 152, 162, or 172; and b) detecting the presence of CD22 wherein the

presence of CD222 diagnoses for CD22 diagnoses for aa CD22-related CD22-related disease disease in in the the mammal. mammal.

In another embodiment, a method of inhibiting CD22-dependent T cell inhibition, is

provided comprising contacting a cell with a human anti-CD22 antibody or fragment thereof,

wherein the antibody or a fragment thereof comprises an amino acid sequence selected from the

group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142,

152, 162, or 172. In one embodiment, the cell is selected from the group consisting of a CD22-

expressing tumor cell, a tumor-associated macrophage, and any combination thereof.

In another embodiment, a method of blocking T-cell inhibition mediated by a CD22-

expressing cell and altering the tumor microenvironment to inhibit tumor growth in a mammal, is

provided comprising administering to the mammal an effective amount of a composition

comprising an isolated anti-CD22 antibody or fragment thereof, wherein the antibody or a

fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID

NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, and 172. In one

embodiment, embodiment,the cell the is selected cell from from is selected the group the consisting of a CD19-expressing group consisting tumor cell, tumor of a CD19-expressing a cell, a

tumor-associated macrophage, and any combination thereof.

In another embodiment, a method of inhibiting, suppressing or preventing

immunosuppression of an anti-tumor or anti-cancer immune response in a mammal, is provided

comprising administering to the mammal an effective amount of a composition comprising an

isolated anti-CD22 antibody or fragment thereof, wherein the antibody or a fragment thereof

comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22,

32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162 and 172. In one embodiment, the

antibody or fragment thereof inhibits the interaction between a first cell with a T cell, wherein the

first cell is selected from the group consisting of a CD22-expressing tumor cell, a tumor-

associated macrophage, and any combination thereof.

In another aspect, a method is provided for inducing an anti-tumor immunity in a mammal

comprising administering to the mammal a therapeutically effective amount of a T cell transduced

with vector or nucleic acid molecule encoding a disclosed CAR.

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In another embodiment, a method of treating or preventing cancer in a mammal is

provided comprising administering to the mammal one or more of the disclosed CARs, in an

amount effective to treat or prevent cancer in the mammal. The method includes administering to

the subject a therapeutically effective amount of host cells expressing a disclosed CAR that

specifically binds CD222 and/or one CD22 and/or one or or more more of of the the aforementioned aforementioned antigens, antigens, under under conditions conditions

sufficient to form an immune complex of the antigen binding domain on the CAR and the

extracellular domain of CD22 and/or one or more of the aforementioned antigens in the subject.

In yet another embodiment, a method is provided for treating a mammal having a disease,

disorder or condition associated with an elevated expression of a tumor antigen, the method

comprising administering to the subject a pharmaceutical composition comprising an anti-tumor

effective amount of a population of T cells, wherein the T cells comprise a nucleic acid sequence

that encodes a CAR, wherein the CAR includes at least one extracellular CD22 antigen binding

domain comprising the amino acid sequence of SEQ ID NOs. 2, 12, 22, 32, 42, 52, 62, 72, 82, 92,

102, 112, 122, 132, 142, 152, 162, or 172, or any combination thereof, at least one linker or spacer

domain, at least one transmembrane domain, at least one intracellular signaling domain, and

wherein the T cells are T cells of the subject having cancer.

In yet another embodiment, a method is provided for treating cancer in a subject in need

thereof comprising administering to the subject a pharmaceutical composition comprising an anti-

tumor effective amount of a population of T cells, wherein the T cells comprise a nucleic acid

sequence that encodes a CAR, wherein the CAR comprises at least one CD222 antigen binding CD22 antigen binding

domain, at least one transmembrane domain, at least one intracellular signaling domain, wherein

the T cells are T cells of the subject having cancer. In some embodiments of the aforementioned

methods, the at least one transmembrane domain comprises a transmembrane the alpha, beta or

zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16,

CD19, CD22, Mesothelin, CD33, CD37, CD64, CD80, CD83, CD86, CD134, CD137, CD154,

TNFRSF16, TNFRSF19, or TNFRSF TNFRSF19, or aa combination combination thereof. thereof. In yet another embodiment, a method is provided for generating a persisting population of

genetically engineered T cells in a human diagnosed with cancer. In one embodiment, the method

comprises administering to a human a T cell genetically engineered to express a CAR wherein the

CAR comprises at least one CD22 antigen binding domain comprising the amino acid sequence of

SEQ ID NOs. 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, or 172, or

any combination thereof, at least one transmembrane domain, and at least one intracellular

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signaling domain wherein the persisting population of genetically engineered T cells, or the

population of progeny of the T cells, persists in the human for at least one month, two months,

three months, four months, five months, six months, seven months, eight months, nine months, ten

months, eleven months, twelve months, two years, or three years after administration.

In one embodiment, the progeny T cells in the human comprise a memory T cell. In

another embodiment, the T cell is an autologous T cell.

In all of the aspects and embodiments of methods described herein, any of the

aforementioned cancers, diseases, disorders or conditions associated with an elevated expression

of a tumor antigen that may be treated or prevented or ameliorated using one or more of the CARs

disclosed herein,

In yet another aspect, a kit is provided for making a CAR T-cell as described supra or for

preventing, treating, or ameliorating any of the cancers, diseases, disorders or conditions

associated with an elevated expression of a tumor antigen in a subject as described supra,

comprising a container comprising any one of the nucleic acid molecules, vectors, host cells, or

compositions disclosed supra or any combination thereof, and instructions for using the kit.

It will be understood that the CARs, host cells, nucleic acids, and methods are useful

beyond the specific aspects and embodiments that are described in detail herein. The foregoing

features and advantages of the disclosure will become more apparent from the following detailed

description, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 depicts a schematic of the general domain structure of CARs with novel

extracellular CD22 antigen binding domain sequences. A CAR is composed of an extracellular

CD22-binding ScFv domain, a CD8 spacer and transmembrane domain, an intracellular signaling

CD137 costimulatory domain and CD3 zeta signaling domain.

FIGURES 2A-R depict several CARs containing novel extracellular CD22 antigen binding

domain sequences. The general scheme for the CARs includes, from the N terminus to the C

terminus, a Signal peptide, anti-CD22 binder variable heavy chain fragment or a linked single

chain fragment variable (ScFv), extracellular linker, transmembrane, 4-1BB, CD3 zeta.

FIGURE 2A depicts a lentiviral vector expressing the CAR containing the LTG 2202 16P

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 3) and the encoded

amino acid sequence (SEQ ID NO: 4).

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FIGURE 2B depicts a lentiviral vector expressing the CAR containing the LTG 2246 24P

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 13) and the encoded

amino acid sequence (SEQ ID NO: 14).

FIGURE 2C depicts a lentiviral vector expressing the CAR containing the LTG 2247 25P

CD22ScFv-CD8 TM-41BB-CD3zeta nucleotide sequence (SEQ ID NO: 23) and the encoded

amino acid sequence (SEQ ID NO: 24).

FIGURE 2D depicts a lentiviral vector expressing the CAR containing the LTG 2248 11s

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 33) and the encoded amino acid amino acidsequence. sequence

FIGURE 2E depicts a lentiviral vector expressing the CAR containing the LTG 2249 12s

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 43) and the encoded

amino acid sequence (SEQ ID NO: 44).

FIGURE 2F depicts a lentiviral vector expressing the CAR containing the LTG 2203 16P3

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 53) and the encoded

amino acid sequence (SEQ ID NO: 54).

FIGURE 2G depicts a lentiviral vector expressing the CAR containing the LTG 2204 16P16

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 63) and the encoded

amino acid sequence (SEQ ID NO: 64).

FIGURE 2H depicts a lentiviral vector expressing the CAR containing the LTG 2205 16P20

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 73) and the encoded

amino acid sequence (SEQ ID NO: 74).

FIGURE 2I depicts a lentiviral vector expressing the CAR containing the LTG 2206 16P2

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 83) and the encoded

amino acid sequence (SEQ ID NO: 84).

FIGURE 2J depicts a lentiviral vector expressing the CAR containing the LTG 2207 16P6

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 93) and the encoded

amino acid sequence (SEQ ID NO: 94).

FIGURE 2K depicts a lentiviral vector expressing the CAR containing the LTG 2208 16P10

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 103) and the encoded

amino acid sequence (SEQ ID NO: 104).

FIGURE 2L depicts a lentiviral vector expressing the CAR containing the LTG 2209 16P17

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 113) and the encoded

amino acid sequence (SEQ ID NO: 114).

PCT/US2018/056011

FIGURE 2M depicts a lentiviral vector expressing the CAR containing the LTG 2210

16P20v2 CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 123) and the

encoded amino acid sequence (SEQ ID NO: 124).

FIGURE 2N depicts a lentiviral vector expressing the CAR containing the LTG 2216 16P1

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 133) and the encoded

amino acid sequence (SEQ ID NO: 134).

FIGURE 20 depicts a lentiviral vector expressing the CAR containing the LTG 2217 16P3v2

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 143) and the encoded

amino acid sequence (SEQ ID NO: 144).

FIGURE 2P depicts a lentiviral vector expressing the CAR containing the LTG 2218 16P8

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 153) and the encoded

amino acid sequence (SEQ ID NO: 154).

FIGURE 2Q depicts a lentiviral vector expressing the CAR containing the LTG 2219 16P13

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 163) and the encoded

amino acid sequence (SEQ ID NO: 164).

FIGURE 2R depicts a lentiviral vector expressing the CAR containing the LTG 2220 16P15

CD22ScFv-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 173) and the encoded

amino acid sequence (SEQ ID NO: 174).

FIGURE 3 depicts Anti-CD22 CART surface expression in primary human T cells. CAR T

cells redirected to CD22 tumor antigen via the use of ScFv domains (as listed in each row of the

figure) were generated by lentiviral transduction with CAR expression constructs. CART

detection was performed by flow cytometry. T cells were washed twice in cold PBS-EDTA

buffer and stained with CD22-Fc peptide followed by anti Fc-PE reagent. At least 20,000 cells

were acquired for each analysis. Cells were gated based on forward scatter and side scatter,

singlet discrimination, and 7AAD negativity SO so that only viable cells were analyzed. Data were

acquired on MACSQuant 10 flow cytometer (Miltenyi Biotec, Inc.). The vertical dotted line

running through the panel identifies the CAR-expressing population (those falling to the right of

this gate). At the top of the panel untransduced cells (UTD) are shown as a negative control and

immediately below, in the second row, cells transduced with the m971 positive control are shown.

Subsequent rows show CAR expression for each vector construct listed on the left axis of the

figure. Results are representative of T cell transductions in three donors.

FIGURE 4 depicts anti CD22 CAR T cells incorporating ScFv binders (16P, 16P1, 16P3v2,

16P8, 16P10, 16P13, 16P15, 16P17), utd=untransduced negative control, m971= previously

published anti-CD22 CAR positive control) mediating cytolysis of CD22-positive tumors in vitro.

19

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CAR T cells expressing anti-CD22 constructs were incubated with CD22-positive cell lines (Raji

and Reh), or CD19-negative lines (K562 and 293T) that were stably transduced with firefly

luciferase, at effector to target ratio of 1.25, 2.5, 5, 10, 20, and 40 (x-axis) overnight. Then,

CART cytotoxic activity was assessed by luciferase activity measurement as described in the

Materials and Methods. Each bar is the mean of 3 technical replicates and error bars represent

SD. Representative of at least three separate experiments.

FIGURE 5 depicts CD22-specifc CART cell production of three cytokines (interferon-

gamma, TNF-alpha, and IL-2) when co-cultured alone (medium gray, CAR only), with CD22-

positive leukemia lines (Raji, black bars, Reh, light gray), or a CD22-negative line (293T, pale

gray). The assay was carried out overnight at E:T ratio of 10:1, then supernatants were analyzed

for cytokine concentrations by ELISA. N=3 +SEM. Negative control: untransduced T cells (utd),

positive control: transduced m971 CD22 CAR-T cells. LTG numbers of each LV used to transduce human T cells are listed on the x-axis.

FIGURE 6 shows two-dimensional flow cytometric analysis of CAR expression on the surface

of T cells transduced with LV to express: no CAR (UTD), or LTG2200, 2202, 2216, 2206, 2217,

2207, 2218, 2208, 2219, 2220, 2209, 2205, control GFP-expressing vector, or control CAR-19

(LTG1538), as shown reading down the rows, left to right, and listed above each plot. The y-axis

dimension shows staining for CD4 and the x-axis dimension shows CAR expression by virtue of

staining with target antigen (CD22-Fc recombinant protein (R&D Biosystems), secondarily stained

with anti-Fc PE antibody).

FIGURES 7A-B show cytolytic activity (CTL activity) as percent lysis of target cell lines that

each express luciferase.

FIGURE 7A shows the CD22 positive cell lines Raji and Reh and the CD22 non-expressing

line K562.

FIGURE 7B shows K562-CD19 and K562-CD22 cell lines, which were specifically transfected

to express the target antigens. Three effector to target ratios were tested (E:T 10:1, 5:1, 2.5:1) for

each LV-transduced T cell population, as listed on the x-axis: utd (untransduced, GFP-LV,

LTG1538 (anti-CD19), m971 (LTG2200, control anti-CD22), 16p (LTG2202), 16p1 (LTG2216),

16p2 (LTG2206), 16p3v2 (LTG2217), 16p6 (LTG2207), 16p8 (LTG2218), 16p10 (LTG2208),

16p13 (LTG2219), 16p15 (LTG2220), 16p17 (TG2209), 16p20 (LTG2205).

FIGURE 8 shows the production of IFN-gamma (top), IL-2 (middle), and TNF-alpha (lower

panel) by anti-CD22 CART cells upon co-incubated with CD22-positive Raji and Reh leukemia

cell lines (black or gray bars, respectively), or without target tumor cells (T cells only), overnight

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at E:T ratio of 10:1, then supernatants analyzed for cytokine concentration by ELISA. CAR only

negative control groups were used to assess spontaneous cytokine secretion by CAR T cells.

Representative of at least three separate experiments. CAR-T activity is illustrated, as listed on the

x-axis, for untransduced T cells (utd), T cells transduced with GFP-LV (GFP), CD19-CAR

(LTG1538), CD22 control CAR (LTG2220, m971), 16p (LTF2202), 16p1 (LTG2216), 16p2

(LTG2206), (LTG2206),16p3v2 16p3v2(LTG2217), 16p616p6 (LTG2217), (LTG2207), 16p8 (LTG2218), (LTG2207), 16p10 (LTG2208), 16p8 (LTG2218), 16p13 16p10 (LTG2208), 16p13

(LTG2219), 16p15 (LTG2220), 16p17 (LTG2209), 16p20 (LTG2205), or leukemia targets incubated without CAR T cells (tumor only).

FIGURE 9 shows the ability of CAR T specific for CD22 to control disease in an animal

model. Immunodeficient mice (NSG) were injected i.v. with Raji leukemia cells that stably

express firefly luciferase on study day 0. The disease burden is measured on the x-axis, reported

as average radiance for each group, following injection with the luciferase substrate luciferin and

imaged in an IVIS instrument that images each animal. Animals were assigned to equivalent

disease burden groups of 6 mice each on day 6 and injected with CAR T cells on day 7 and disease

progression was followed over time. Animals infused with Raji cells and not treated with T cells

(TA, open circle) progressed rapidly and had to be sacrificed by day 21. Other groups received

untransduced T cells (UTD, open square), CAR-19 transduced T cells (1538 CAR 19, open

triangle), control anti-CD22 CAR (2200 m971, -x-), new CAR LTG2209 (2209 16P17, open

diamond), new CAR LTG2219 (2219 16P13, open inverted triangle)

DETAILED DESCRIPTION

Definitions

As used herein, the singular forms "a," "an," and "the," refer to both the singular as well as

plural, unless the context clearly indicates otherwise. For example, the term "an antigen" includes

single or plural antigens and can be considered equivalent to the phrase "at least one antigen." As

used herein, the term "comprises" means "includes." Thus, "comprising an antigen" means

"including an antigen" without excluding other elements. The phrase "and/or" means "and" or

"or." It is further to be understood that any and all base sizes or amino acid sizes, and all

molecular weight or molecular mass values, given for nucleic acids or polypeptides are

approximate, and are provided for descriptive purposes, unless otherwise indicated. Although

many methods and materials similar or equivalent to those described herein can be used, particular

WO wo 2019/079249 PCT/US2018/056011

suitable methods and materials are described below. In case of conflict, the present specification,

including explanations of terms, will control. In addition, the materials, methods, and examples

are illustrative only and not intended to be limiting. To facilitate review of the various

embodiments, the following explanations of terms are provided:

The term "about" when referring to a measurable value such as an amount, a temporal

duration, and the like, is meant to encompass variations of ++.20% +-.20% or in some instances .10%, +-.10%,

or in some instances ++.5%, +-.5%, or in some instances +-.1%, or in some instances ++.0.1% +-.0.1% from the

specified value, as such variations are appropriate to perform the disclosed methods.

Unless otherwise noted, the technical terms herein are used according to conventional

usage. Definitions of common terms in molecular biology can be found in Benjamin Lewin,

Genes VII, published by Oxford University Press, 1999; Kendrew et al. (eds.), The Encyclopedia

of Molecular Biology, published by Blackwell Science Ltd., 1994; and Robert A. Meyers (ed.),

Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH

Publishers, Inc., 1995; and other similar references.

The present disclosure provides for CD22 antibodies or fragments thereof as well as CARs

having such CD22 antigen binding domains. The enhancement of the functional activity of the

CAR directly relates to the enhancement of functional activity of the CAR-expressing T cell. As a

result of one or more of these modifications, the CARs exhibit both a high degree of cytokine-

induced cytolysis and cell surface expression on transduced T cells, along with an increased level

of in vivo T cell expansion and persistence of the transduced CAR-expressing T cell.

The unique ability to combine functional moieties derived from different protein domains

has been a key innovative feature of CARs. The choice of each of these protein domains is a key

design feature, as is the way in which they are specifically combined. Each design domain is an

essential component that can be used across different CAR platforms to engineer the function of

lymphocytes. For example, the choice of the extracellular binding domain can make an otherwise

ineffective CAR be effective.

The invariable framework components of the immunoglobulin-derived protein sequences

used to create the extracellular antigen binding domain of a CAR can either be entirely neutral, or

they can self-associate and drive the T cell to a state of metabolic exhaustion, thus making the

therapeutic T cell expressing that CAR far less effective. This occurs independently of the

antigen binding function of this CAR domain. Furthermore, the choice of the intracellular

signaling domain(s) also can govern the activity and the durability of the therapeutic lymphocyte

population used for immunotherapy. While the ability to bind target antigen and the ability to

transmit an activation signal to the T cell through these extracellular and intracellular domains, respectively, are important CAR design aspects, what has also become apparent is that the choice of the source of the extracellular antigen binding fragments can have a significant effect on the efficacy of the CAR and thereby have a defining role for the function and clinical utility of the

CAR. Surprisingly and unexpectedly it has now been discovered that use of an entirely human

antigen binding domain in a CAR, rather than using mouse-derived antigen binding fragments

which are prone to induce anti-mouse immune response and CAR T elimination in a host (c.f., the

UPenn-sponsored clinical trial using mouse derived SS1 ScFv sequence, NCT02159716), may

also determine the functional activity of a CAR-expressing T cell.

The CARs disclosed herein are expressed at a high level in a cell. A cell expressing the

CAR has a high in vivo proliferation rate, produces large amounts of cytokines, and has a high

cytotoxic activity against a cell having, on its surface, a CD22 antigen to which a CAR binds. The

use of a human extracellular CD22 antigen binding domain results in generation of a CAR that

functions better in vivo, while avoiding the induction of anti-CAR immunity in the host immune

response and the killing of the CAR T cell population. The CARs expressing the entirely human

extracellular CD22 ScFv antigen binding domain exhibit superior activities/properties including i)

prevention of poor CAR T persistence and function as seen with mouse-derived binding

sequences; ii) lack of regional (i.e. intrapleural) delivery of the CAR to be efficacious; and iii)

ability to generate CAR T cell designs based both on binders with high and low affinity to CD19.

This latter property allows investigators to better tune efficacy vs VS toxicity, and/or tissue specificity

of the CAR T product, since lower-affinity binders may have higher specificity to tumors VS vs

normal tissues due to higher expression of CD222 ontumors CD22 on tumorsthan thannormal normaltissue, tissue,which whichmay may

prevent on-target off tumor toxicity and bystander cell killing.

What follows is a detailed description of the inventive CARs including a description of

their extracellular CD22 antigen binding domain, the transmembrane domain and the intracellular

domain, along with additional description of the CARs, antibodies and antigen binding fragments

thereof, conjugates, nucleotides, expression, vectors, and host cells, methods of treatment,

compositions, and kits employing the disclosed CARs.

A. Chimeric Antigen Receptors (CARs)

The CARs disclosed herein comprise at least one CD22 antigen binding domain capable of

binding to CD22, at least one transmembrane domain, and at least one intracellular domain.

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A chimeric antigen receptor (CAR) is an artificially constructed hybrid protein or

polypeptide containing the antigen binding domains of an antibody (e.g., single chain variable

fragment (ScFv)) linked to T-cell signaling domains via the transmembrane domain. Characteristics of CARs include their ability to redirect T-cell specificity and reactivity toward a

selected target in a non-Major Histocompatibiliy Complex (MHC)-restricted manner, and

exploiting the antigen-binding properties of monoclonal antibodies. The non-MHC-restricted

antigen recognition gives T cells expressing CARs the ability to recognize antigen independent of

antigen processing, thus bypassing a major mechanism of tumor escape. Moreover, when

expressed in T-cells, CARs advantageously do not dimerize with endogenous T cell receptor

(TCR) alpha and beta chains.

As disclosed herein, the intracellular T cell signaling domains of the CARs can include,

for example, a T cell receptor signaling domain, a T cell costimulatory signaling domain, or both.

The T cell receptor signaling domain refers to a portion of the CAR comprising the intracellular

domain of a T cell receptor, such as, for example, and not by way of limitation, the intracellular

portion of the CD3 zeta protein. The costimulatory signaling domain refers to a portion of the

CAR comprising the intracellular domain of a costimulatory molecule, which is a cell surface

molecule other than an antigen receptor or their ligands that are required for an efficient response

of lymphocytes to antigen.

1. Extracellular Domain

In one embodiment, the CAR comprises a target-specific binding element otherwise

referred to as an antigen binding domain or moiety. The choice of domain depends upon the type

and number of ligands that define the surface of a target cell. For example, the antigen binding

domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells

associated with a particular disease state. Thus examples of cell surface markers that may act as

ligands for the antigen binding domain in the CAR include those associated with viral, bacterial

and parasitic infections, autoimmune disease and cancer cells.

In one embodiment, the CAR can be engineered to target a tumor antigen of interest by

way of engineering a desired antigen binding domain that specifically binds to an antigen on a

tumor cell. Tumor antigens are proteins that are produced by tumor cells that elicit an immune

response, particularly response, particularly T-cell T-cell mediated mediated immuneimmune responses responses. The selection The selection of thebinding of the antigen antigen binding

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domain will depend on the particular type of cancer to be treated. Tumor antigens include, for

example, a glioma-associated antigen, carcinoembryonic antigen (CEA), beta.-human chorionic

gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX,

human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxyl esterase, mut hsp70-

2, M-CSF, prostase, prostate-specific antigen (PSA), PAP, NY-ESO-1, LAGE-1a, p53, prostein,

PSMA, Her2/neu, survivin and telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1),

MAGE, ELF2M, neutrophil elastase, ephrinB2, CD19, insulin growth factor (IGF)-I, IGF-II, IGF-

I receptor and CD22. The tumor antigens disclosed herein are merely included by way of

example. The list is not intended to be exclusive and further examples will be readily apparent to

those of skill in the art.

In one embodiment, the tumor antigen comprises one or more antigenic cancer epitopes

associated with a malignant tumor. Malignant tumors express a number of proteins that can serve

as target antigens for an immune attack. These molecules include, but are not limited to, tissue-

specific antigens such as MART-1, tyrosinase and GP 100 in melanoma and prostatic acid

phosphatase (PAP) and prostate-specific antigen (PSA) in prostate cancer. Other target molecules

belong to the group of transformation-related molecules such as the oncogene HER-2/Neu/ErbB-

2. Yet another group of target antigens are onco-fetal antigens such as carcinoembryonic antigen

(CEA). In B-cell lymphoma the tumor-specific idiotype immunoglobulin constitutes a truly

tumor-specific immunoglobulin antigen that is unique to the individual tumor. B-cell

differentiation antigens such as CD19, CD20, CD22, BCMA, RORI, ROR1, and CD37 are other

candidates for target antigens in B-cell lymphoma. Some of these antigens (CEA, HER-2, CD19,

CD20, CD22, idiotype) have been used as targets for passive immunotherapy with monoclonal

antibodies with limited success.

In one preferred embodiment, the tumor antigen is CD22 and the tumors associated with

expression of CD22 comprise lung mesothelioma, ovarian, and pancreatic cancers that express

high levels of the extracellular protein CD22, or any combination thereof.

The type of tumor antigen may also be a tumor-specific antigen (TSA) or a tumor-

associated antigen (TAA). A TSA is unique to tumor cells and does not occur on other cells in the

body. A TAA is not unique to a tumor cell and instead is also expressed on a normal cell under

conditions that fail to induce a state of immunologic tolerance to the antigen. The expression of

the antigen on the tumor may occur under conditions that enable the immune system to respond to

the antigen. TAAs may be antigens that are expressed on normal cells during fetal development

when the immune system is immature and unable to respond or they may be antigens that are

WO wo 2019/079249 PCT/US2018/056011

normally present at extremely low levels on normal cells but which are expressed at much higher

levels on tumor cells.

Non-limiting examples of TSAs or TAAs include the following: Differentiation antigens

such as MART-1/MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2 and tumor-

specific multi-lineage antigens such as MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15;

overexpressed embryonic antigens such as CEA; overexpressed oncogenes and mutated tumor-

suppressor genes such as p53, Ras, HER-2/neu; unique tumor antigens resulting from

chromosomal translocations; such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR; and

viral antigens, such as the Epstein Barr virus antigens EBVA and the human papillomavirus

(HPV) antigens E6 and E7. Other large, protein-based antigens include TSP-180, MAGE-4,

MAGE-5, MAGE-6, RAGE, NY-ESO, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72,

CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, beta-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F,

5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125, CA 15-3\CA

27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\P1, CO-029, FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90\Mac-2 binding protein\cyclophilin C-associated protein, TAAL6, TAG72,

TLP, and TPS.

In one embodiment, the antigen binding domain portion of the CAR targets an antigen that

includes but is not limited to CD19, CD20, CD22, RORI, ROR1, CD33, CD38, CD123, CD138, BCMA,

c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, FGFR4, TSLPR, NY-ESO-1 TCR, MAGE A3 TCR, and the like.

In a preferred embodiment, the antigen binding domain portion of the CAR targets the

extracellular CD222 antigen. CD22 antigen.

In one preferred embodiment, the isolated nucleic acid molecule encoding the extracellular

CD22 scFv1 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 1, or a

sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof. In one embodiment, an

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 2, or an amino acid sequence

with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to an amino acid sequence of SEQ ID NO:

2.

CD22 scFv2 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 11, or a

PCT/US2018/056011

binding domain comprises an amino acid sequence of SEQ ID NO: 12, or an amino acid sequence

12.

CD222 ScFv3 antigen CD22 ScFv3 antigen binding binding domain domain comprises comprises aa nucleotide nucleotide sequence sequence of of SEQ SEQ ID ID NO: NO: 21, 21, or or aa

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv3 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 22, or an amino acid sequence

22.

CD22 ScFv4 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 31, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv4 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 32, or an amino acid sequence

32.

CD22 ScFv5 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 41, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv5 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 42, or an amino acid sequence

42.

CD22 ScFv6 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 51, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv6 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 52, or an amino acid sequence

52.

CD22 ScFv7 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 61, or a

PCT/US2018/056011

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv7 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 62, or an amino acid sequence

62.

CD22 ScFv8 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 71, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv8 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 72, or an amino acid sequence

72.

CD22 ScFv9 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 81, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv9 antigen

binding domain comprises an amino acid sequence of SEQ ID NO: 82, or an amino acid sequence

82.

CD22 ScFv10 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 91, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv10

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 92, or an amino acid

sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to an amino acid sequence of

SEQ ID NO: 92.

CD22 ScFv11 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 101, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv102

SEQ ID NO: 102.

CD22 ScFv12 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 111, or a

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isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv112

SEQ ID NO: 112.

CD22 ScFv13 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 121, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv13

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid

SEQ ID NO: 122.

CD222 ScFv14 antigen CD22 ScFv14 antigen binding binding domain domain comprises comprises aa nucleotide nucleotide sequence sequence of of SEQ SEQ ID ID NO: NO: 131, 131, or or aa

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv14

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 132, or an amino acid

SEQ ID NO: 132.

CD22 ScFv15 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 141, or a

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv15

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 142, or an amino acid

SEQ ID NO: 142.

CD22 CD22 ScFv16 ScFv16 antigen antigen binding binding domain domain comprises comprises aa nucleotide nucleotide sequence sequence of of SEQ SEQ ID ID NO: NO: 151, 151, or or aa

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv16

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 152, or an amino acid

SEQ ID NO: 152.

CD222 ScFv17 antigen CD22 ScFv17 antigen binding binding domain domain comprises comprises aa nucleotide nucleotide sequence sequence of of SEQ SEQ ID ID NO: NO: 161, 161, or or aa

isolated nucleic acid molecule is provided wherein the encoded extracellular CD222 ScFv17 CD22 ScFv17

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 162, or an amino acid

SEQ ID NO: 162.

CD22 ScFv18 antigen binding domain comprises a nucleotide sequence of SEQ ID NO: 171, or a a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof. In one embodiment, an

isolated nucleic acid molecule is provided wherein the encoded extracellular CD22 ScFv18

antigen binding domain comprises an amino acid sequence of SEQ ID NO: 172, or an amino acid

SEQ ID NO: 172.

In one preferred embodiment, the isolated light chain complementarity determining region

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 5, SEQ ID NO: 6,

and SEQ ID NO: 7, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 8, SEQ ID NO: 9, and SEQ

ID ID NO: NO: 10, 10, respectively) respectively) that that each each individually individually contribute contribute to to create create the the binding binding characerisitcs characerisitcs of of

the CD22 specific scFv1, as a grouping to create the light chain binding characteristic of the scFv

(LCDR1 plus LCDR2 plus LCDR3), as a grouping to create the heavy chain binding

charactersitics of the scFv (HCDR1 plus HCDR2 plus HCDR3), and as a grouping of six SEQ IDs

that together as a group create the binding characterictics of the CD22 specific scFv1 by co-

expression expression ofofSEQ SEQ ID ID NO:NO: 5, SEQ 5, SEQ IDNO:6,SEQID ID NO: NO:7,SEQID 6, SEQ ID NO: 7, SEQ ID NO:8,SEQ NO: 8, SEQID ID NO: NO: 9, and and

SEQ ID NO: 10, in a single ScFv amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 15, SEQ ID NO: 16,

and SEQ ID NO: 17, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 18, SEQ ID NO: 19, and

SEQ ID NO: 20, respectively) that each individually contribute to create the binding characerisitcs

of the CD22 specific scFv2, as a grouping to create the light chain binding characteristic of the

scFv (LCDR1 plus LCDR2 plus LCDR3), as a grouping to create the heavy chain binding

that together as a group create the binding characterictics of the CD22 specific scFv2 by co-

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expression of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID

NO:19, NO: and SEQ 19, and SEQIDIDNO: NO: 20,20, in in a single a single aminoamino acid sequence. acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 25, SEQ ID NO: 26,

and SEQ ID NO: 27, respectively) and the heavy chain complementarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 28, SEQ ID NO: 29,

and SEQ ID NO: 30, respectively) that each individually contribute to create the binding

characerisitcs of the CD22 specific scFv3, as a grouping to create the light chain binding

characteristic of the scFv (LCDR1 plus LCDR2 plus LCDR3), as a grouping to create the heavy

chain binding charactersitics of the scFv (HCDR1 plus HCDR2 plus HCDR3), and as a grouping

of six SEQ IDs that together as a group create the binding characterictics of the CD22 specific

scFv3 by co-expression of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28,

SEQ ID NO: 29, and SEQ ID NO: 30, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 35, SEQ ID NO: 36,

and SEQ ID NO: 37, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 38, SEQ ID NO: 39, and

SEQ ID NO: 40, respectively) that each individually contribute to create the binding characerisites characerisitcs

of the CD22 specific scFv4, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD22 specific scFv4 by co-

expression of SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO:

39, and SEQ ID NO: 40, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 45, SEQ ID NO: 46,

and SEQ ID NO: 47, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 48, SEQ ID NO: 49, and

SEQ ID NO: 50, respectively) that each individually contribute to create the binding characerisitcs

of the CD22 specific scFv5, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD22 specific scFv5 by co-

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expression of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO:

49, and SEQ ID NO: 50, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 55, SEQ ID NO: 56,

and SEQ ID NO: 57, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 58, SEQ ID NO: 59, and

SEQ ID NO: 60, respectively) that each individually contribute to create the binding characerisites characerisitcs

of the CD22 specific scFv6, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD22 specific scFv6 by co-

expression of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO:

59, and SEQ ID NO: 60, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 65, SEQ ID NO: 66,

and SEQ ID NO: 67, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 68, SEQ ID NO: 69, and

SEQ ID NO: 70, respectively) that each individually contribute to create the binding characerisites characerisitcs

of the CD22 specific scFv7, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD22 specific scFv7 by co-

expression of SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO:

69, and SEQ ID NO: 70, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 75, SEQ ID NO: 76,

and SEQ ID NO: 77, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 78, SEQ ID NO: 79, and

SEQ ID NO: 80, respectively) that each individually contribute to create the binding characerisitcs

of the CD22 specific scFv8, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD222 specific scFv8 CD22 specific scFv8 by by co- co-

PCT/US2018/056011

expression of SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO:

79, and SEQ ID NO: 80, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 85, SEQ ID NO: 86,

and SEQ ID NO: 87, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 88, SEQ ID NO: 89, and

SEQ ID NO: 90, respectively) that each individually contribute to create the binding characerisites characerisitcs

of the CD22 specific scFv9, as a grouping to create the light chain binding characteristic of the

that together as a group create the binding characterictics of the CD22 specific scFv9 by co-

expression of SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO:

89, and SEQ ID NO: 90, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 95, SEQ ID NO: 96,

and SEQ ID NO: 97, respectively) and the heavy chain complmentarity determining region amino

acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 98, SEQ ID NO: 99, and

SEQ ID NO: 100, respectively) that each individually contribute to create the binding

characerisitcs of the CD222 specificscFv10, CD22 specific scFv10,as asaagrouping groupingto tocreate createthe thelight lightchain chainbinding binding

of six SEQ IDs that together as a group create the binding characterictics of the CD222 specific CD22 specific

scFv10 by co-expression of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98,

SEQ ID NO: 99, and SEQ ID NO: 100, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 105, SEQ ID NO:

106, and SEQ ID NO: 107, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 108, SEQ ID NO:

109, 109, and and SEQ SEQ ID ID NO: NO: 110, 110, respectively) respectively) that that each each individually individually contribute contribute to to create create the the binding binding

characerisitcs of the CD22 specific scFv11, as a grouping to create the light chain binding

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scFv11 by co-expression of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO:

108, SEQ ID NO: 109, and SEQ ID NO: 110, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 115, SEQ ID NO:

116, and SEQ ID NO: 117, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 118, SEQ ID NO:

119, and SEQ ID NO: 120, respectively) that each individually contribute to create the binding

characerisitcs of the CD22 specific scFv12, as a grouping to create the light chain binding

scFv12 by co-expression of SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO:

118, 118, SEQ SEQ ID ID NO: NO: 119, 119, and and SEQ SEQ ID ID NO: NO: 120, 120, in in aa single single amino amino acid acid sequence. sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 125, SEQ ID NO:

126, and SEQ ID NO: 127, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 128, SEQ ID NO:

129, 129, and and SEQ SEQ ID ID NO: NO: 130, 130, respectively) respectively) that that each each individually individually contribute contribute to to create create the the binding binding

characerisitcs of the CD22 specific scFv13, as a grouping to create the light chain binding

scFv13 by co-expression of SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO:

128, SEQ ID NO: 129, and SEQ ID NO: 130, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 135, SEQ ID NO:

136, and SEQ ID NO: 137, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 138, SEQ ID NO:

139, and SEQ ID NO: 140, respectively) that each individually contribute to create the binding

characerisitcs of the CD22 specific scFv14, as a grouping to create the light chain binding

PCT/US2018/056011

scFv14 by co-expression of SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ NO:137, SEQ ID ID NO: NO:

138, 138, SEQ SEQ ID ID NO: NO: 139, 139, and and SEQ SEQ ID ID NO: NO: 140, 140, in in aa single single amino amino acid acid sequence. sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 145, SEQ ID NO:

146, and SEQ ID NO: 147, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 148, SEQ ID NO:

149, and SEQ ID NO: 150, respectively) that each individually contribute to create the binding

characerisitcs of the CD22 specific scFv15, as a grouping to create the light chain binding

scFv15 by co-expression of SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO:

148, 148, SEQ SEQ ID ID NO: NO: 149, 149, and and SEQ SEQ ID ID NO: NO: 150, 150, in in aa single single amino amino acid acid sequence. sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 155, SEQ ID NO:

156, and SEQ ID NO: 157, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 158, SEQ ID NO:

159, 159, and and SEQ SEQ ID ID NO: NO: 160, 160, respectively) respectively) that that each each individually individually contribute contribute to to create create the the binding binding

characerisitcs of the CD22 specific scFv16, as a grouping to create the light chain binding

scFv16 by co-expression of SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO:

158, SEQ ID NO: 159, and SEQ ID NO: 160, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 165, SEQ ID NO:

166, and SEQ ID NO: 167, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 168, SEQ ID NO:

169, 169, and and SEQ SEQ ID ID NO: NO: 170, 170, respectively) respectively) that that each each individually individually contribute contribute to to create create the the binding binding

characerisitcs of the CD22 specific scFv17, as a grouping to create the light chain binding

PCT/US2018/056011

scFv17 by co-expression of SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO:

168, SEQ ID NO: 169, and SEQ ID NO: 170, in a single amino acid sequence.

amino acid sequences (LCDR1, LCDR2, LCDR2, identified as SEQ ID NO: 175, SEQ ID NO:

176, and SEQ ID NO: 177, respectively) and the heavy chain complmentarity determining region

amino acid sequences (HCDR1, HCDR2, HCDR3, identified as SEQ ID NO: 178, SEQ ID NO:

179, and SEQ ID NO: 180, respectively) that each individually contribute to create the binding

characerisitcs of the CD22 specific scFv18, as a grouping to create the light chain binding

scFv18 by co-expression of SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO:

178, 178, SEQ SEQ ID ID NO: NO: 179, 179, and and SEQ SEQ ID ID NO: NO: 180, 180, in in aa single single amino amino acid acid sequence. sequence.

In the various embodiments of the CD22-specific CARs disclosed herein, the general

scheme is set forth in FIGURE 1 and includes, from the N-terminus to the C-terminus, a signal or

leader peptide, anti-CD22 ScFv, extracellular linker, CD8 transmembrane, 4-1BB, CD3zeta,

wherein the bolded text represents the cloning sites for linking domains.

sequence of SEQ ID NO: 3, and encodes the CAR comprising the amino acid sequence as set

forth in SEQ ID NO: 4 [LTG 2202 LP-16P-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2A)].

sequence of SEQ ID NO: 3, or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity

thereof, and encodes the CAR comprising the amino acid sequence as set forth in SEQ ID NO: 4

or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof, LTG 2202 LP-16P-

CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2A)].

acid sequence of SEQ ID NO: 13 and encodes the CAR comprising the amino acid sequence as

set forth in SEQ ID NO: 14 [LTG 2246 LP-24P-CD8 TM-41BB-CD3zeta amino acid sequence

(as depicted in Figure 2B)].

acid sequence of SEQ ID NO: 13 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99%

identity thereof, and encodes the CAR comprising the amino acid sequence as set forth in SEQ ID

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NO: 14 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof [LTG 2246

LP-24P-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2B)].

acid sequence of SEQ ID NO: 23, and encodes the CAR comprising the amino acid sequence as

set forth in SEQ ID NO: 24 [LTG 2247 LP-25P-CD8 TM-41BB-CD3zeta CAR amino acid sequence (as depicted in Figure 2C)].

acid sequence of SEQ ID NO: 23 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99%

NO: 24 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof [LTG 2247

LP-25P-CD8 TM-41BB-CD3zeta CAR amino acid sequence (as depicted in Figure 2C)].

In yet another embodiment, the nucleic acid sequence encoding a CAR comprises the

nucleic acid sequence of SEQ ID NO: 33, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 34 [LTG2248 LP-11S-CD8 TM-41BB-CD3zeta amino acid

sequence (as depicted in Figure 2D)].

nucleic acid sequence of SEQ ID NO: 33 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

99% identity thereof, and encodes the CAR comprising the amino acid sequence as set forth in

SEQ ID NO: 34 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[LTG2248 LP-11S-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2D)].

nucleic acid sequence of SEQ ID NO: 43, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 44 [LTG2249 LP-12S-CD8 TM-41BB-CD3zeta amino acid

sequence (as depicted in Figure 2E)].

nucleic acid sequence of SEQ ID NO: 43 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 44 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[LTG2249 LP-12S-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2E)].

nucleic acid sequence of SEQ ID NO: 53, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 54 [(LTG2203 LP-16P3-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2F)].

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nucleic acid sequence of SEQ ID NO: 53 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 54 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[LTG2203 LP-16P3-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2F)].

nucleic acid sequence of SEQ ID NO: 63, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 64 [(LTG2204 LP-16P16-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2G)].

nucleic acid sequence of SEQ ID NO: 63 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 64 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2204 LP-16P16-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2G)].

nucleic acid sequence of SEQ ID NO: 73, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 74 [(LTG2205 LP-16P20-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2H)].

nucleic acid sequence of SEQ ID NO: 73 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 74 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2205 LP-16P20-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2H)].

nucleic acid sequence of SEQ ID NO: 83, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 84 [(LTG2206 LP-16P2-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2I)].

nucleic acid sequence of SEQ ID NO: 83 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 84 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2206 LP-16P2-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2I)].

nucleic acid sequence of SEQ ID NO: 93, and encodes the CAR comprising the amino acid

PCT/US2018/056011

sequence as set forth in SEQ ID NO: 94 [(LTG2207 LP-16P6-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2J)].

nucleic acid sequence of SEQ ID NO: 93 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or

SEQ ID NO: 94 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2207 LP-16P6-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2J)].

nucleic acid sequence of SEQ ID NO: 103, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 104 [(LTG2208 LP-16P10-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2K)].

nucleic acid sequence of SEQ ID NO: 103 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

or 99% identity thereof, and encodes the CAR comprising the amino acid sequence as set forth in

SEQ ID NO: 104 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2208 LP-16P10-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2K)].

nucleic acid sequence of SEQ ID NO: 113, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 114 [(LTG2209 LP-16P17-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2L)].

nucleic acid sequence of SEQ ID NO: 113 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 114 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2209 LP-16P17-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2L)].

nucleic acid sequence of SEQ ID NO: 123, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 124 [(LTG2210 LP-16P20v2-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2M)].

nucleic acid sequence of SEQ ID NO: 123 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 124 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

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[(LTG2210 LP-16P20y2-CD8 LP-16P20v2-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure

2M)].

nucleic acid sequence of SEQ ID NO: 133, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 134 [(LTG2216 LP-16P1-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2N)].

nucleic acid sequence of SEQ ID NO: 133 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 134 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2216 LP-16P1-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2N)].

nucleic acid sequence of SEQ ID NO: 143, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 144 [(LTG2217 LP-16P3v2-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 20)].

nucleic acid sequence of SEQ ID NO: 143 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 144 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2217 LP-16P17-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 20)].

nucleic acid sequence of SEQ ID NO: 153, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 154 [(LTG2218 LP-16P8-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2P)].

nucleic acid sequence of SEQ ID NO: 153 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 154 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2218 LP-16P8-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2P)].

nucleic acid sequence of SEQ ID NO: 163, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 164 [(LTG2219 LP-16P13-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2Q)].

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nucleic acid sequence of SEQ ID NO: 163 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 164 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2219 LP-16P13-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2Q)].

nucleic acid sequence of SEQ ID NO: 173, and encodes the CAR comprising the amino acid

sequence as set forth in SEQ ID NO: 174 [(LTG2220 LP-16P15-CD8 TM-41BB-CD3zeta amino

acid sequence (as depicted in Figure 2R)].

nucleic acid sequence of SEQ ID NO: 173 or a sequence with 85%, 90%, 95%, 96%, 97%, 98%

SEQ ID NO: 174 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity thereof

[(LTG2220 LP-16P15-CD8 TM-41BB-CD3zeta amino acid sequence (as depicted in Figure 2R)].

The surface expression of anti-CD22 CARs incorporating single chain fragment variable

(ScFv) sequences reactive with CD22 antigen, is shown in Example 2 infra and summarized in

Table 2, Table 3, and Figure 6. The expression level for each ScFv-containing CAR was

determined by flow cytometric analysis of LV-transduced T cells from healthy donors using a

recombinant CD22-Fc peptide, followed by anti-human Fc F(ab')2 fragment conjugated to PE,

and detected by flow cytometry, (c.f., Figure 6). The ScFv-based anti-CD22 CAR constructs

LTG2202, LTG2216, LTG2217, LTG2218, LTG2208, LTG2219, LTG2220, and LTG2209 were highly expressed in human primary T cells (as indicated by the gated population) as compared to

non-transduced T cell controls (non-gated cell population, UTD). Representative results from one

donor are shown.

As shown in Example 2 and Figure 4, 7A, and 7B, high cytolytic activity of the CD222 CD22

CARs was demonstrated when lentiviral vectors (LV) expressing the following CARs were

created and tested for anti-leukemia activity. Each experimental CAR contains the 4-1BB/CD3-

zeta chain signaling motif and the specific anti-CD22 binding motif/domain noted therein.

Leukemia target lines with varying CD22 surface expression were used: Raji and Reh; and CD19

negative K562 and 293T. ScFv-based anti-CD22 CAR constructs LTG2202, LTG2216,

LTG2217, LTG2218, LTG2208, LTG2219, LTG220, and LTG2209, expressing scFv1 (16P),

ScFv2 (16P1), scFv3 (16P3v2), scFv3 (16P3v2), scFv4 (16P8), scFv5 (16P10), scFv6 (16P13),

scFv7 (16P15), scFv8 (16P17), respectively, were able to efficiently lyse CD22-high tumor lines

Raji and Reh, whereas they had little or no specific lytic activity against K562 or 293T, (c.f.,

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Figure 4, 7A, 7B). These results demonstrate the efficiency and specificity of the generated CAR

constructs.

The capacity of anti-CD22 CAR T cells for cytokine secretion was then evaluated. Tumor

cells were co-incubated with CAR T cells or control T cells at effector to target ratio of 10:1

overnight, and culture supernatants were analyzed by ELISA for IFN gamma, TNF alpha and IL-2

(c.f., Figure 8). Of note, CAR T-cells transduced with LTG2202, LTG2216, LTG2217,

LTG2218, LTG2208, LTG2219, LTG2220, and LTG2209, expressing scFv1 (16P), ScFv2

(16P1), scFv3 (16P3v2), scFv3 (16P3v2), scFv4 (16P8), scFv5 (16P10), scFv6 (16P13), scFv7

(16P15), scFv8 (16P17), respectively, elaborated high levels of IFN gamma, whereas the negative

control (untransduced, utd) yielded no appreciable cytokine induction. However, clear differences

in, TNF-alpha and IL-2 production were seen. Surprisingly, CD22 CAR LTG2202, yielded

significantly lower levels of TNF-alpha and IL-2, against the Reh tumor line, and each vector had

a differential ability to produce IL-2 and TNF-alpha to the tumor line targets tested. These

differences will result in different anti-tumor and toxicity profiles, and will be individually

implemented according to the disease burden, in specific disease settings. The CAR used as a

positive control, m971, was used to benchmark results, as it is currently in clinical trials and, thus

far, is safe for use in advanced disease settings.

Without being intended to limit to any particular mechanism of action, it is believed that

possible reasons for the enhanced therapeutic function associated with the exemplary CARs of the

invention include, for example, and not by way of limitation, a) improved lateral movement

within the plasma membrane allowing for more efficient signal transduction, b) superior location

within plasma membrane microdomains, such as lipid rafts, and greater ability to interact with

transmembrane signaling cascades associated with T cell activation, c) superior location within

the plasma membrane by preferential movement away from dampening or down-modulatory

interactions, such as less proximity to or interaction with phosphatases such as CD45, and d)

superior assembly into T cell receptor signaling complexes (i.e. the immune synapse), or any

combination thereof.

While the disclosure has been illustrated with an exemplary extracellular CD22 variable

heavy chain only and ScFv antigen binding domains, other nucleotide and/or amino acid variants

within the CD22 variable heavy chain only and ScFv antigen binding domains may be used to

derive the CD22 antigen binding domains for use in the CARs described herein.

Depending on the desired antigen to be targeted, the CAR can be additionally engineered

to include the appropriate antigen binding domain that is specific to the desired antigen target.

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For example, if CD22 is the desired antigen that is to be targeted, an antibody for CD22 can be

used as the antigen bind domain incorporation into the CAR.

In one exemplary embodiment, the antigen binding domain portion of the CAR

additionally targets CD33. Preferably, the antigen binding domain in the CAR is anti-CD33

heavy chain only binder VH-4, wherein the nucleic acid sequence of the anti-CD33 heavy chain-

only binder comprises the sequence set forth in SEQ ID NO: 202. In one embodiment, the anti-

CD33 heavy chain-only binder comprises the nucleic acid sequence that encodes the amino acid

sequence of SEQ ID NO: 202. In another embodiment, the anti-CD33 heavy chain only portion

of the CAR comprises the amino acid sequence set forth in SEQ ID NO: 203. In another

exemplary embodiment, the nucleic acid sequence of the CAR expressing anti-CD33 heavy chain

only binder, LTG1906 is comprised of SEQ ID: 204. In another embodiment, the amino acid

sequence of anti-CD33 heavy chain only binder expressing CAR LTG1906 is comprised of SEQ

ID NO: 205.

In one exemplary embodiment, the antigen binding domain portion of the CAR

additionally targets mesothelin. Preferably, the antigen binding domain in the CAR is anti-

mesothelin ScFv, wherein the nucleic acid sequence of the anti-mesothelin ScFv comprises the

sequence set forth in SEQ ID NO: 198. In one embodiment, the anti-mesothelin ScFv comprises

the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 199. In another

embodiment, the anti-mesothelin ScFv portion of the CAR comprises the amino acid sequence set

forth in SEQ ID NO: 199. In another exemplary embodiment, the nucleic acid sequence of the

CAR expressing the anti-mesothelin scFv is comprised of SEQ ID: 200. In another embodiment,

the amino acid sequence of the anti-mesothelin CAR LTG1904 is set forth in SEQ ID NO: 201

In one aspect of the present invention, there is provided a CAR capable of binding to a

non-TSA or non-TAA including, for example and not by way of limitation, an antigen derived

from Retroviridae (e.g. human immunodeficiency viruses such as HIV-1 and HIV-LP), Picornaviridae (e.g. poliovirus, hepatitis A virus, enterovirus, human coxsackievirus, rhinovirus,

and echovirus), rubella virus, coronavirus, vesicular stomatitis virus, rabies virus, ebola virus,

parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus, influenza virus,

hepatitis B virus, parvovirus, Adenoviridae, Herpesviridae [e.g. type 1 and type 2 herpes simplex

virus (HSV), varicella-zoster virus, cytomegalovirus (CMV), and herpes virus], Poxviridae (e.g.

smallpox virus, vaccinia virus, and pox virus), or hepatitis C virus, or any combination thereof.

In another aspect of the present invention, there is provided a CAR capable of binding to

an antigen derived from a bacterial strain of Staphylococci, Streptococcus, Escherichia coli,

Pseudomonas, or Salmonella. Particularly, there is provided a CAR capable of binding to an

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antigen derived from an infectious bacterium, for example, Helicobacter pyloris, Legionella

pneumophilia, a bacterial strain of Mycobacteria sps. (e.g. M. tuberculosis, M. avium, M.

intracellulare, M. kansaii, or M. gordonea), Staphylococcus aureus, Neisseria gonorrhoeae,

Neisseria meningitides, Listeria monocytogenes, Streptococcus pyogenes, Group A Streptococcus, Group B Streptococcus (Streptococcus agalactiae), Streptococcus pneumoniae, or

Clostridium tetani, or a combination thereof.

2. Transmembrane Domain 2. Transmembrane Domain

With respect to the transmembrane domain, the CAR comprises one or more transmembrane domains transmembrane fused domains to the fused to extracellular CD22 antigen the extracellular binding domain CD22 antigen of domain binding the CAR.of the CAR

The transmembrane domain may be derived either from a natural or from a synthetic

source. Where the source is natural, the domain may be derived from any membrane-bound or

transmembrane protein.

Transmembrane regions of particular use in the CARs described herein may be derived

from (i.e. comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-

cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, mesothelin,

CD33, CD37, CD64, CD80, CD83, CD86, CD134, CD137, CD154, TNFRSF16, or TNFRSF19.

Alternatively the transmembrane domain may be synthetic, in which case it will comprise

predominantly hydrophobic residues such as leucine and valine. Preferably a triplet of

phenylalanine, tryptophan and valine will be found at each end of a synthetic transmembrane

domain. Optionally, a short oligo- or polypeptide linker, preferably between 2 and 10 amino acids

in length may form the linkage between the transmembrane domain and the cytoplasmic signaling

domain of the CAR. A glycine-serine doublet provides a particularly suitable linker.

In one embodiment, the transmembrane domain that naturally is associated with one of the

domains in the CAR is used in addition to the transmembrane domains described supra.

In some instances, the transmembrane domain can be selected or by amino acid

substitution to avoid binding of such domains to the transmembrane domains of the same or

different surface membrane proteins to minimize interactions with other members of the receptor

complex.

In one embodiment, the transmembrane domain in the CAR of the invention is the CD8

transmembrane domain. In one embodiment, the CD8 transmembrane domain comprises the

nucleic acid sequence of SEQ ID NO: 181. In one embodiment, the CD8 transmembrane domain

comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 182.

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In another embodiment, the CD8 transmembrane domain comprises the amino acid sequence of

SEQ ID NO: 182.

In one embodiment, the encoded transmembrane domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20,

10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 182, or a

sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 182.

In some instances, the transmembrane domain of the CAR comprises the CD8. alpha.hinge CD8.alpha.hinge

domain. In one embodiment, the CD8 hinge domain comprises the nucleic acid sequence of SEQ

ID NO: 183. In one embodiment, the CD8 hinge domain comprises the nucleic acid sequence that

encodes the amino acid sequence of SEQ ID NO: 184. In another embodiment, the CD8 hinge

domain comprises the amino acid sequence of SEQ ID NO: 184, or a sequence with 95-99%

identify thereof.

linker domain is derived from the extracellular domain of CD8, and is linked to the

transmembrane CD8 domain, the transmembrane CD28 domain, or a combination thereof.

3. Spacer Domain

In the CAR, a spacer domain can be arranged between the extracellular domain and the

transmembrane domain, or between the intracellular domain and the transmembrane domain. The

spacer domain means any oligopeptide or polypeptide that serves to link the transmembrane

domain with the extracellular domain and/or the transmembrane domain with the intracellular

domain. The spacer domain comprises up to 300 amino acids, preferably 10 to 100 amino acids,

and most preferably 25 to 50 amino acids.

In several embodiments, the linker can include a spacer element, which, when present,

increases the size of the linker such that the distance between the effector molecule or the

detectable marker and the antibody or antigen binding fragment is increased. Exemplary spacers

are known to the person of ordinary skill, and include those listed in U.S. Pat. Nos. 7,964,566,

7,498,298, 6,884,869, 6,323,315, 6,239,104, 6,034,065, 5,780,588, 5,665,860, 5,663,149,

5,635,483, 5,599,902, 5,554,725, 5,530,097, 5,521,284, 5,504,191, 5,410,024, 5,138,036,

5,076,973, 4,986,988, 4,978,744, 4,879,278, 4,816,444, and 4,486,414, as well as U.S. Pat. Pub.

Nos. 20110212088 and 20110070248, each of which is incorporated by reference herein in its

entirety.

The spacer domain preferably has a sequence that promotes binding of a CAR with an

antigen and enhances signaling into a cell. Examples of an amino acid that is expected to promote

the binding include cysteine, a charged amino acid, and serine and threonine in a potential

glycosylation site, and these amino acids can be used as an amino acid constituting the spacer

domain.

As the spacer domain, the entire or a part of amino acid numbers 137-206 (SEQ ID NO:

39) which is a hinge region of CD8.alpha. (NCBI RefSeq: NP.sub.--001759.3), amino acid

numbers 135 to 195 of CD8.beta. (GenBank: AAA35664.1), amino acid numbers 315 to 396 of

CD4 (NCBI RefSeq: NP.sub.--000607.1), or amino acid numbers 137 to 152 of CD28 (NCBI

RefSeq: NP.sub.--006130.1) can be used. Also, as the spacer domain, a part of a constant region

of an antibody H chain or L chain can be used. Further, the spacer domain may be an artificially

synthesized sequence.

Further, in the CAR, a signal peptide sequence can be linked to the N-terminus. The

signal peptide sequence exists at the N-terminus of many secretory proteins and membrane

proteins, and has a length of 15 to 30 amino acids. Since many of the protein molecules

mentioned above as the intracellular domain have signal peptide sequences, the signal peptides

can be used as a signal peptide for the CAR. In one embodiment, the signal peptide comprises the

amino acid sequence shown in SEQ ID NO: 191.

4. Intracellular Domain

The cytoplasmic domain or otherwise the intracellular signaling domain of the CAR is

responsible for activation of at least one of the normal effector functions of the immune cell in

which the CAR has been placed in. The term "effector function" refers to a specialized function

of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity

including the secretion of cytokines. Thus the term "intracellular signaling domain" refers to the

portion of a protein which transduces the effector function signal and directs the cell to perform a

specialized function. While usually the entire intracellular signaling domain can be employed, in

many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the

intracellular signaling domain is used, such truncated portion may be used in place of the intact

chain as long as it transduces the effector function signal. The term intracellular signaling domain

is thus meant to include any truncated portion of the intracellular signaling domain sufficient to

transduce the effector function signal.

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Preferred examples of intracellular signaling domains for use in the CAR include the

cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate

signal transduction following antigen receptor engagement, as well as any derivative or variant of

these sequences and any synthetic sequence that has the same functional capability.

It is known that signals generated through the TCR alone are insufficient for full activation

of the T cell and that a secondary or co-stimulatory signal is also required. Thus, T cell activation

can be said to be mediated by two distinct classes of cytoplasmic signaling sequence: those that

initiate antigen-dependent primary activation through the TCR (primary cytoplasmic signaling

sequences) and those that act in an antigen-independent manner to provide a secondary or co-

stimulatory signal (secondary cytoplasmic signaling sequences).

Primary cytoplasmic signaling sequences regulate primary activation of the TCR complex

either in a stimulatory way, or in an inhibitory way. Primary cytoplasmic signaling sequences that

act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor

tyrosine-based activation motifs or ITAMs.

Examples of ITAM containing primary cytoplasmic signaling sequences that are of

particular use in the CARS disclosed herein include those derived from TCR zeta (CD3 Zeta),

FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, and

CD66d. Specific, non-limiting examples, of the ITAM include peptides having sequences of

amino acid numbers 51 to 164 of CD3.zeta. (NCBI RefSeq: NP.sub.--932170.1), amino acid

numbers 45 to 86 of Fc.epsilon.RT.gamma Fc.epsilon.RI.gamma.(NCBI (NCBIRefSeq: RefSeq:NP.sub.--004097.1), NP.sub.--004097.1),amino aminoacid acid

numbers 201 to 244 of Fc.epsilon.RI.beta. (NCBI RefSeq: NP.sub.--000130.1), amino acid

numbers 139 to 182 of CD3.gamma. (NCBI RefSeq: NP.sub.--000064.1), amino acid numbers

128 to 171 of CD3 .delta. (NCBI RefSeq: delta. (NCBI RefSeq: NP.sub.--000723.1), NP.sub.--000723.1), amino amino acid acid numbers numbers 153 153 to to 207 207

of CD3.epsilon. (NCBI RefSeq: NP.sub.--000724.1), amino acid numbers 402 to 495 of CD5

(NCBI RefSeq: NP.sub.--055022.2), amino acid numbers 707 to 847 of 0022 (NCBI RefSeq:

NP.sub.--001762.2), amino NP.sub.--001762.2), amino acid acid numbers numbers 166 166 to to 226 226 of of CD79a CD79a (NCBI (NCBI RefSeq: RefSeq: NP.sub.-- NP.sub.--

001774.1), amino acid numbers 182 to 229 of CD79b (NCBI RefSeq: NP.sub.--000617.1), and

amino acid numbers 177 to 252 of CD66d (NCBI RefSeq: NP.sub.--001806.2), and their variants

having the same function as these peptides have. The amino acid number based on amino acid

sequence information of NCBI RefSeq ID or GenBank described herein is numbered based on the

full length of the precursor (comprising a signal peptide sequence etc.) of each protein. In one

embodiment, the cytoplasmic signaling molecule in the CAR comprises a cytoplasmic signaling

sequence derived from CD3 zeta.

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In a preferred embodiment, the intracellular domain of the CAR can be designed to

comprise the CD3-zeta signaling domain by itself or combined with any other desired cytoplasmic

domain(s) useful in the context of the CAR. For example, the intracellular domain of the CAR

can comprise a CD3 zeta chain portion and a costimulatory signaling region. The costimulatory

signaling region refers to a portion of the CAR comprising the intracellular domain of a

costimulatory molecule. A costimulatory molecule is a cell surface molecule other than an

antigen receptor or their ligands that is required for an efficient response of lymphocytes to an

antigen. Examples of such costimulatory molecules include CD27, CD28, 4-1BB (CD137),

OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2,

CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like.

Specific, non-limiting examples, of such costimulatory molecules include peptides having

sequences of amino acid numbers 236 to 351 of CD2 (NCBI RefSeq: NP.sub.--001758.2), amino

acid numbers 421 to 458 of CD4 (NCBI RefSeq RefSeq:NP.sub.--000607.1), NP.sub.--000607.1),amino aminoacid acidnumbers numbers402 402to to

495 of CD5 (NCBI RefSeq: NP.sub.--055022.2), amino acid numbers 207 to 235 of CD8.alpha.

(NCBI RefSeq: NP.sub.--001759.3), amino acid numbers 196 to 210 of CD83 (GenBank:

AAA35664.1), amino acid numbers 181 to 220 of CD28 (NCBI RefSeq: NP.sub.--006130.1),

amino acid numbers 214 to 255 of CD137 (4-1BB, NCBI RefSeq: NP.sub.--001552.2), amino

acid numbers 241 to 277 of CD134 (OX40, NCBI RefSeq: NP.sub.--003318.1), and amino acid

numbers 166 to 199 of ICOS (NCBI RefSeq: NP.sub.--036224.1), and their variants having the

same function as these peptides have. Thus, while the disclosure herein is exemplified primarily

with 4-1BB as the co-stimulatory signaling element, other costimulatory elements are within the

scope of the disclosure.

The cytoplasmic signaling sequences within the cytoplasmic signaling portion of the CAR

may be linked to each other in a random or specified order. Optionally, a short oligo- or

polypeptide linker, preferably between 2 and 10 amino acids in length may form the linkage. A

glycine-serine doublet provides a particularly suitable linker.

In one embodiment, the intracellular domain is designed to comprise the signaling domain

of CD3-zeta and the signaling domain of CD28. In another embodiment, the intracellular domain

is designed to comprise the signaling domain of CD3-zeta and the signaling domain of 4-1BB. In

yet another embodiment, the intracellular domain is designed to comprise the signaling domain of

CD3-zeta and the signaling domain of CD28 and 4-1BB.

In one embodiment, the intracellular domain in the CAR is designed to comprise the

signaling domain of 4-1BB and the signaling domain of CD3-zeta, wherein the signaling domain

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of 4-1BB comprises the nucleic acid sequence set forth in SEQ ID NO: 186 and the signaling

domain of CD3-zeta comprises the nucleic acid sequence set forth in SEQ ID NO: 188.

of 4-1BB comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID

NO: 187 and the signaling domain of CD3-zeta comprises the nucleic acid sequence that encodes

the amino acid sequence of SEQ ID NO: 189.

of 4-1BB comprises the amino acid sequence set forth in SEQ ID NO: 187 and the signaling

domain of CD3-zeta comprises the amino acid sequence set forth in SEQ ID NO: 189.

5. Additional Description of CARs

Also expressly included within the scope of the invention are functional portions of the

CARs disclosed herein. The term "functional portion" when used in reference to a CAR refers to

any part or fragment of one or more of the CARs disclosed herein, which part or fragment retains

the biological activity of the CAR of which it is a part (the parent CAR). Functional portions

encompass, for example, those parts of a CAR that retain the ability to recognize target cells, or

detect, treat, or prevent a disease, to a similar extent, the same extent, or to a higher extent, as the

parent CAR. In reference to the parent CAR, the functional portion can comprise, for instance,

about 10%, 25%, 30%, 50%, 68%, 80%, 90%, 95%, or more, of the parent CAR.

The functional portion can comprise additional amino acids at the amino or carboxy

terminus of the portion, or at both termini, which additional amino acids are not found in the

amino acid sequence of the parent CAR. Desirably, the additional amino acids do not interfere

with the biological function of the functional portion, e.g., recognize target cells, detect cancer,

treat or prevent cancer, etc. More desirably, the additional amino acids enhance the biological

activity, as compared to the biological activity of the parent CAR.

Included in the scope of the disclosure are functional variants of the CARs disclosed

herein. The term "functional variant" as used herein refers to a CAR, polypeptide, or protein

having substantial or significant sequence identity or similarity to a parent CAR, which functional

variant retains the biological activity of the CAR of which it is a variant. Functional variants

encompass, for example, those variants of the CAR described herein (the parent CAR) that retain

the ability to recognize target cells to a similar extent, the same extent, or to a higher extent, as the

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parent CAR. In reference to the parent CAR, the functional variant can, for instance, be at least

about 30%, 50%, 75%, 80%, 90%, 98% or more identical in amino acid sequence to the parent

CAR. A functional variant can, for example, comprise the amino acid sequence of the parent

CAR with at least one conservative amino acid substitution. Alternatively or additionally, the

functional variants can comprise the amino acid sequence of the parent CAR with at least one

non-conservative amino acid substitution. In this case, it is preferable for the non-conservative

amino acid substitution to not interfere with or inhibit the biological activity of the functional

variant. The non-conservative amino acid substitution may enhance the biological activity of the

functional variant, such that the biological activity of the functional variant is increased as

compared to the parent CAR.

Amino acid substitutions of the CARs are preferably conservative amino acid substitutions. Conservative amino acid substitutions are known in the art, and include amino acid

substitutions in which one amino acid having certain physical and/or chemical properties is

exchanged for another amino acid that has the same or similar chemical or physical properties.

For instance, the conservative amino acid substitution can be an acidic/negatively charged polar

amino acid substituted for another acidic/negatively charged polar amino acid (e.g., Asp or Glu),

an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side

chain (e.g., Ala, Gly, Val, He, Leu, Met, Phe, Pro, Trp, Cys, Val, etc.), a basic/positively charged

polar amino acid substituted for another basic/positively charged polar amino acid (e.g. Lys, His,

Arg, etc.), an uncharged amino acid with a polar side chain substituted for another uncharged

amino acid with a polar side chain (e.g., Asn, Gin, Ser, Thr, Tyr, etc.), an amino acid with a beta-

branched side-chain substituted for another amino acid with a beta-branched side-chain (e.g., He,

Thr, and Val), an amino acid with an aromatic side-chain substituted for another amino acid with

an aromatic side chain (e.g., His, Phe, Trp, and Tyr), etc.

The CAR can consist essentially of the specified amino acid sequence or sequences

described herein, such that other components, e.g., other amino acids, do not materially change

the biological activity of the functional variant.

The CARs (including functional portions and functional variants) can be of any length,

i.e., can comprise any number of amino acids, provided that the CARs (or functional portions or

functional variants thereof) retain their biological activity, e.g., the ability to specifically bind to

antigen, detect diseased cells in a mammal, or treat or prevent disease in a mammal, etc. For

example, the CAR can be about 50 to about 5000 amino acids long, such as 50, 70, 75, 100, 125,

150, 175, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more amino acids in length.

WO wo 2019/079249 PCT/US2018/056011

The CARs (including functional portions and functional variants of the invention) can

comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such

synthetic amino acids are known in the art, and include, for example, aminocyclohexane

carboxylic acid, norleucine, -amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine,

trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4- nitrophenylalanine, 4-

chlorophenylalanine, 4-carboxyphenylalanine, B-phenylserine ß-phenylserine B-hydroxyphenylalanine, ß-hydroxyphenylalanine,

phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic

acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid

monoamide, N'-benzyl-N'-methyl-lysine, N',N'-dibenzyl-lysine, 6-hydroxylysine, ornithine, - -

aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane

carboxylic acid, a-(2-amino-2-norbornane)-carboxylic acid, y-diaminobutyric acid, - ß-

diaminopropionic acid, homophenylalanine, and a-tert-butylglycine.

The CARs (including functional portions and functional variants) can be glycosylated,

amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via, e.g., a disulfide

bridge, or converted into an acid addition salt and/or optionally dimerized or polymerized, or

conjugated.

The CARs (including functional portions and functional variants thereof) can be obtained

by methods known in the art. The CARs may be made by any suitable method of making polypeptides or proteins. Suitable methods of de novo synthesizing polypeptides and proteins are

described in references, such as Chan et al., Fmoc Solid Phase Peptide Synthesis, Oxford

University Press, Oxford, United Kingdom, 2000; Peptide and Protein Drug Analysis, ed. Reid,

R., Marcel Dekker, Inc., 2000; Epitope Mapping, ed. Westwood et al., Oxford University Press,

Oxford, United Kingdom, 2001; and U.S. Patent 5,449,752. Also, polypeptides and proteins can

be recombinantly produced using the nucleic acids described herein using standard recombinant

methods. See, for instance, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed.,

Cold Spring Harbor Press, Cold Spring Harbor, NY 2001; and Ausubel et al., Current Protocols in

Molecular Biology, Greene Publishing Associates and John Wiley & Sons, NY, 1994. Further,

some of the CARs (including functional portions and functional variants thereof) can be isolated

and/or purified from a source, such as a plant, a bacterium, an insect, a mammal, e.g., a rat, a

human, etc. Methods of isolation and purification are well-known in the art. Alternatively, the

CARs described herein (including functional portions and functional variants thereof) can be

commercially synthesized by companies. In this respect, the CARs can be synthetic, recombinant,

isolated, and/or purified.

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B. Antibodies and Antigen Binding Fragments

One embodiment further provides a CAR, a T cell expressing a CAR, an antibody, or

antigen binding domain or portion thereof, which specifically binds to one or more of the antigens

disclosed herein. As used herein, a "T cell expressing a CAR," or a "CAR T cell" means a T cell

expressing a CAR, and has antigen specificity determined by, for example, the antibody-derived

targeting domain of the CAR.

As used herein, and "antigen binding domain" can include an antibody and antigen

binding fragments thereof. The term "antibody" is used herein in the broadest sense and

encompasses various antibody structures, including but not limited to monoclonal antibodies,

polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), and antigen binding

fragments thereof, SO so long as they exhibit the desired antigen-binding activity. Non-limiting

examples of antibodies include, for example, intact immunoglobulins and variants and fragments

thereof known in the art that retain binding affinity for the antigen.

A "monoclonal antibody" is an antibody obtained from a population of substantially

homogeneous antibodies, i.e., the individual antibodies comprising the population are identical

except for possible naturally occurring mutations that may be present in minor amounts.

Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. The

modifier "monoclonal" indicates the character of the antibody as being obtained from a

substantially homogeneous population of antibodies, and is not to be construed as requiring

production of the antibody by any particular method. In some examples, a monoclonal antibody is

an antibody produced by a single clone of B lymphocytes or by a cell into which nucleic acid

encoding the light and heavy variable regions of the antibody of a single antibody (or an antigen

binding fragment thereof) have been transfected, or a progeny thereof. In some examples

monoclonal antibodies are isolated from a subject. Monoclonal antibodies can have conservative

amino acid substitutions which have substantially no effect on antigen binding or other

immunoglobulin functions. Exemplary methods of production of monoclonal antibodies are

known, for example, see Harlow & Lane, Antibodies, A Laboratory Manual, 2nd ed. Cold Spring

Harbor Publications, New York (2013).

Typically, an immunoglobulin has heavy (H) chains and light (L) chains interconnected by

disulfide bonds. Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon

and mu constant region genes, as well as the myriad immunoglobulin variable domain genes.

There There are aretwo types two of of types light chain, light lambdalambda chain, (2) and()kappa and (k). kappaThere (k).are five are There main five heavymain chainheavy chain

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classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD,

IgG, IgA and IgE.

Each heavy and light chain contains a constant region (or constant domain) and a variable

region region(or (orvariable domain; variable see, see, domain; e.g.,e.g., Kindt Kindt et al. et Kuby Immunology, al. 6th ed., W.H. Kuby Immunology, Freeman 6 ed., W.H.and Freeman and

Co., page 91 (2007).) In several embodiments, the heavy and the light chain variable regions

combine to specifically bind the antigen. In additional embodiments, only the heavy chain

variable region is required. For example, naturally occurring camelid antibodies consisting of a

heavy chain only are functional and stable in the absence of light chain (see, e.g., Hamers-

Casterman et al., Nature, 363:446-448, 1993; Sheriff et al., Nat. Struct. Biol., 3:733-736, 1996).

References to "VH" or "VH" refer to the variable region of an antibody heavy chain, including

that of an antigen binding fragment, such as Fv, ScFv, dsFv or Fab. References to "VL" or "VL"

refer to the variable domain of an antibody light chain, including that of an Fv, ScFv, dsFv or Fab.

Light and heavy chain variable regions contain a "framework" region interrupted by three

hypervariable regions, also called "complementarity-determining regions" or "CDRs" (see, e.g.,

Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and

Human Services, 1991). The sequences of the framework regions of different light or heavy

chains are relatively conserved within a species. The framework region of an antibody, that is the

combined framework regions of the constituent light and heavy chains, serves to position and

align the CDRs in three-dimensional space.

The CDRs are primarily responsible for binding to an epitope of an antigen. The amino

acid sequence boundaries of a given CDR can be readily determined using any of a number of

well-known schemes, including those described by Kabat et al. ("Sequences of Proteins of

Immunological Interest," 5th Ed. 5 Ed. Public Public Health Health Service, Service, National National Institutes Institutes ofof Health, Health, Bethesda, Bethesda,

MD, 1991; "Kabat" numbering scheme), Al-Lazikani et al., (JMB 273,927-948, 1997; "Chothia"

numbering scheme), and Lefranc et al. ("IMGT unique numbering for immunoglobulin and T cell

receptor variable domains and Ig superfamily V-like domains," Dev. Comp. Immunol., 27:55-77,

2003; "IMGT" numbering scheme). The CDRs of each chain are typically referred to as CDR1,

CDR2, and CDR3 (from the N-terminus to C-terminus), and are also typically identified by the

chain in which the particular CDR is located. Thus, a VH CDR3 is the CDR3 from the variable

domain of the heavy chain of the antibody in which it is found, whereas a VL CDR1 is the CDR1

from the variable domain of the light chain of the antibody in which it is found. Light chain

CDRs are sometimes referred to as LCDR1, LCDR2, and LCDR3. Heavy chain CDRs are

sometimes referred to as HCDR1, HCDR2, and HCDR3.

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An "antigen binding fragment" is a portion of a full length antibody that retains the ability

to specifically recognize the cognate antigen, as well as various combinations of such portions.

Non-limiting examples of antigen binding fragments include Fv, Fab, Fab', Fab'-SH, F(ab')2;

diabodies; linear antibodies; single-chain antibody molecules (e.g. ScFv); and multi-specific

antibodies formed from antibody fragments. Antibody fragments include antigen binding

fragments either produced by the modification of whole antibodies or those synthesized de novo

using recombinant DNA methodologies (see, e.g., Kontermann and Dubel (Ed), Antibody

Engineering, Vols. 1-2, 2nd Ed., Springer Press, 2010).

A single-chain antibody (ScFv) is a genetically engineered molecule containing the VH

and VL domains of one or more antibody(ies) linked by a suitable polypeptide linker as a

genetically fused single chain molecule (see, for example, Bird et al., Science, 242:423 426, 1988;

Huston et al., Proc. Natl. Acad. Sci., 85:5879 5883, 1988; Ahmad et al., Clin. Dev. Immunol.,

2012, doi:10.1155/2012/980250; doi: 10.1155/2012/980250;Marbry, Marbry,IDrugs, IDrugs,13:543-549, 13:543-549,2010). 2010).The Theintramolecular intramolecular

orientation of the VH-domain and the VL-domain in a ScFv, is typically not decisive for ScFvs.

Thus, ScFvs with both possible arrangements (VH-domain-linker domain-VL-domain; VL-

domain-linker domain-VH-domain) may be used.

In a dsFv, the heavy and light chain variable chains have been mutated to introduce a

disulfide bond to stabilize the association of the chains. Diabodies also are included, which are

bivalent, bispecific antibodies in which VH and VL domains are expressed on a single

polypeptide chain, but using a linker that is too short to allow for pairing between the two

domains on the same chain, thereby forcing the domains to pair with complementary domains of

another chain and creating two antigen binding sites (see, for example, Holliger et al., Proc. Natl.

Acad. Sci., 90:6444 6448, 1993; Poljak et al., Structure, 2:1121 1123, 1994).

Antibodies also include genetically engineered forms such as chimeric antibodies (such as

humanized murine antibodies) and heteroconjugate antibodies (such as bispecific antibodies). See

also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, J.,

Immunology, 3rd Ed., W.H. Freeman & Co., New York, 1997.

Non-naturally occurring antibodies can be constructed using solid phase peptide synthesis,

can be produced recombinantly, or can be obtained, for example, by screening combinatorial

libraries consisting of variable heavy chains and variable light chains as described by Huse et al.,

Science 246:1275-1281 (1989), which is incorporated herein by reference. These and other

methods of making, for example, chimeric, humanized, CDR-grafted, single chain, and

bifunctional antibodies, are well known to those skilled in the art (Winter and Harris, Immunol.

Today 14:243-246 (1993); Ward et al., Nature 341:544-546 (1989); Harlow and Lane, supra,

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1988; Hilyard et al., Protein Engineering: A practical approach (IRL Press 1992); Borrabeck,

Antibody Engineering, 2d ed. (Oxford University Press 1995); each of which is incorporated

herein by reference).

An "antibody that binds to the same epitope" as a reference antibody refers to an antibody

that blocks binding of the reference antibody to its antigen in a competition assay by 50% or

more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a

competition assay by 50% or more. Antibody competition assays are known, and an exemplary

competition assay is provided herein.

A "humanized" antibody or antigen binding fragment includes a human framework region

and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) antibody or antigen

binding fragment. The non-human antibody or antigen binding fragment providing the CDRs is

termed a "donor," and the human antibody or antigen binding fragment providing the framework

is termed an "acceptor." In one embodiment, all the CDRs are from the donor immunoglobulin in

a humanized immunoglobulin. Constant regions need not be present, but if they are, they can be

substantially identical to human immunoglobulin constant regions, such as at least about 85-90%,

such as about 95% or more identical. Hence, all parts of a humanized antibody or antigen binding

fragment, except possibly the CDRs, are substantially identical to corresponding parts of natural

human antibody sequences.

A "chimeric antibody" is an antibody which includes sequences derived from two different

antibodies, which typically are of different species. In some examples, a chimeric antibody

includes one or more CDRs and/or framework regions from one human antibody and CDRs

and/or framework regions from another human antibody.

A "fully human antibody" or "human antibody" is an antibody which includes sequences

from (or derived from) the human genome, and does not include sequence from another species.

In some embodiments, a human antibody includes CDRs, framework regions, and (if present) an

Fc region from (or derived from) the human genome. Human antibodies can be identified and

isolated using technologies for creating antibodies based on sequences derived from the human

genome, for example by phage display or using transgenic animals (see, e.g., Barbas et al. Phage

display: A Laboratory Manuel. 1st Ed. New York: Cold Spring Harbor Laboratory Press, 2004.

Print.; Lonberg, Nat. Biotech., 23: 1117-1125, 2005; Lonenberg, Curr. Opin. Immunol., 20:450-

459, 2008). 459,2008).

An antibody may have one or more binding sites. If there is more than one binding site,

the binding sites may be identical to one another or may be different. For instance, a naturally-

occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a bispecific or bifunctional antibody has two different binding sites.

Methods of testing antibodies for the ability to bind to any functional portion of the CAR

are known in the art and include any antibody-antigen binding assay, such as, for example,

radioimmunoassay (RIA), ELISA, Western blot, immunoprecipitation, and competitive inhibition

assays (see, e.g., Janeway et al., infra, U.S. Patent Application Publication No. 2002/0197266 Al,

and U.S. Patent No. 7,338,929).

Also, a CAR, a T cell expressing a CAR, an antibody, or antigen binding portion thereof,

can be modified to comprise a detectable label, such as, for instance, a radioisotope, a fluorophore

(e.g., fluorescein isothiocyanate (FITC), phycoerythrin (PE)), an enzyme (e.g., alkaline

phosphatase, horseradish peroxidase), and element particles (e.g., gold particles).

C. Conjugates

A CAR, a T cell expressing a CAR, or monoclonal antibodies, or antigen binding

fragments thereof, specific for one or more of the antigens disclosed herein, can be conjugated to

an agent, such as an effector molecule or detectable marker, using any number of means known to

those of skill in the art. Both covalent and noncovalent attachment means may be used.

Conjugates include, but are not limited to, molecules in which there is a covalent linkage of an

effector molecule or a detectable marker to an antibody or antigen binding fragment that

specifically binds one or more of the antigens disclosed herein. One of skill in the art will

appreciate that various effector molecules and detectable markers can be used, including (but not

limited to) chemotherapeutic agents, anti-angiogenic agents, toxins, radioactive agents such as

1251, 32P, ¹C, ¹²I, ³²P, 14C, ³H3H and and ³S35S andand other other labels, labels, target target moieties moieties andand ligands, ligands, etc. etc.

The choice of a particular effector molecule or detectable marker depends on the particular

target molecule or cell, and the desired biological effect. Thus, for example, the effector molecule

can be a cytotoxin that is used to bring about the death of a particular target cell (such as a tumor

cell). cell).

The procedure for attaching an effector molecule or detectable marker to an antibody or

antigen binding fragment varies according to the chemical structure of the effector. Polypeptides

typically contain a variety of functional groups; such as carboxylic acid (COOH), free amine (-

NH2) or sulfhydryl (-SH) groups, which are available for reaction with a suitable functional group

on an antibody to result in the binding of the effector molecule or detectable marker.

Alternatively, the antibody or antigen binding fragment is derivatized to expose or attach

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additional reactive functional groups. The derivatization may involve attachment of any of a

number of known linker molecules such as those available from Pierce Chemical Company,

Rockford, IL. The linker can be any molecule used to join the antibody or antigen binding

fragment to the effector molecule or detectable marker. The linker is capable of forming covalent

bonds to both the antibody or antigen binding fragment and to the effector molecule or detectable

marker. Suitable linkers are well known to those of skill in the art and include, but are not limited

to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers.

Where Where the theantibody antibodyor or antigen binding antigen fragment binding and theand fragment effector molecule or the effector detectable molecule marker or detectable marker

are polypeptides, the linkers may be joined to the constituent amino acids through their side

groups (such as through a disulfide linkage to cysteine) or to the alpha carbon amino and carboxyl

groups of the terminal amino acids.

entirety.

In some embodiments, the linker is cleavable under intracellular conditions, such that

cleavage of the linker releases the effector molecule or detectable marker from the antibody or

antigen binding fragment in the intracellular environment. In yet other embodiments, the linker is

not cleavable and the effector molecule or detectable marker is released, for example, by antibody

degradation. In some embodiments, the linker is cleavable by a cleaving agent that is present in

the intracellular environment (for example, within a lysosome or endosome or caveolea). The

linker can be, for example, a peptide linker that is cleaved by an intracellular peptidase or protease

enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments,

the peptide linker is at least two amino acids long or at least three amino acids long. However, the

linker can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids long, such as 1-2, 1-3, 2-5, 3-10,

3-15, 1-5, 1-10, 1-15 amino acids long. Proteases can include cathepsins B and D and plasmin, all

of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug

inside target cells (see, for example, Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-

123). For example, a peptide linker that is cleavable by the thiol-dependent protease cathepsin-B,

PCT/US2018/056011

can be can be used used(for example, (for a Phenylalanine example, -Leucine a Phenylalanine or a Glycine- -Leucine Phenylalanine -Leucine-Glycine or a Glycine-Phenylalanine-Leucine-Glycine

linker). Other examples of such linkers are described, for example, in U.S. Pat. No. 6,214,345,

incorporated herein by reference. In a specific embodiment, the peptide linker cleavable by an

intracellular protease is a Valine-Citruline linker or a Phenylalanine-Lysine linker (see, for

example, U.S. Pat. No. 6,214,345, which describes the synthesis of doxorubicin with the Valine-

Citruline linker). Citruline linker).

In other embodiments, the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at

certain pH values. Typically, the pH-sensitive linker is hydrolyzable under acidic conditions. For

example, an acid-labile linker that is hydrolyzable in the lysosome (for example, a hydrazone,

semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like) can be

used. (See, for example, U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker,

1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such

linkers are relatively stable under neutral pH conditions, such as those in the blood, but are

unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments,

the hydrolyzable linker is a thioether linker (such as, for example, a thioether attached to the

therapeutic agent via an acylhydrazone bond (see, for example, U.S. Pat. No. 5,622,929).

In other embodiments, the linker is cleavable under reducing conditions (for example, a

disulfide linker). A variety of disulfide linkers are known in the art, including, for example, those

that can be formed using SATA (N-succinimidy1-S-acetylthioacetate), (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-

(N-succinimidy1-3-(2-pyridyldithio)butyrate and (2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT SMPT (N- (N-

succinimidyl-oxycarbonyl-alpha-methy1-alpha-(2-pyridy1-dithio)toluene)- SPDB succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene)- SPDB and and SMPT. SMPT.

(See, for example, Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In

Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel

ed., Oxford U. Press, 1987); Phillips et al., Cancer Res. 68:92809290, 2008). See also U.S. Pat.

No. 4,880,935.)

In yet other specific embodiments, the linker is a malonate linker (Johnson et al., 1995,

Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem.

3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12).

In yet other embodiments, the linker is not cleavable and the effector molecule or

detectable marker is released by antibody degradation. (See U.S. Publication No. 2005/0238649

incorporated by reference herein in its entirety).

In several embodiments, the linker is resistant to cleavage in an extracellular environment.

For example, no more than about 20%, no more than about 15%, no more than about 10%, no

more than about 5%, no more than about 3%, or no more than about 1% of the linkers, in a sample

WO wo 2019/079249 PCT/US2018/056011

of conjugate, are cleaved when the conjugate is present in an extracellular environment (for

example, in plasma). Whether or not a linker is resistant to cleavage in an extracellular

environment can be determined, for example, by incubating the conjugate containing the linker of

interest with plasma for a predetermined time period (for example, 2, 4, 8, 16, or 24 hours) and

then quantitating the amount of free effector molecule or detectable marker present in the plasma.

A variety of exemplary linkers that can be used in conjugates are described in WO 2004-010957,

U.S. Publication No. 2006/0074008, U.S. Publication No. 20050238649, and U.S. Publication No.

2006/0024317, each of which is incorporated by reference herein in its entirety.

In several embodiments, conjugates of a CAR, a T cell expressing a CAR, an antibody, or

antigen binding portion thereof, and one or more small molecule toxins, such as a calicheamicin,

maytansinoids, dolastatins, auristatins, a trichothecene, and CC1065, and the derivatives of these

toxins that have toxin activity, are provided.

Maytansine compounds suitable for use as maytansinoid toxin moieties are well known in

the art, and can be isolated from natural sources according to known methods, produced using

genetic engineering techniques (see Yu et al (2002) PNAS 99:7968-7973), or maytansinol and

maytansinol analogues prepared synthetically according to known methods. Maytansinoids are

mitototic inhibitors which act by inhibiting tubulin polymerization. Maytansine was first isolated

from the east African shrub Maytenus serrata (U.S. Pat. No. 3,896,111). Subsequently, it was

discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3

maytansinol esters (U.S. Pat. No. 4,151,042). Synthetic maytansinol and derivatives and

analogues thereof are disclosed, for example, in U.S. Pat. Nos. 4,137,230; 4,248,870; 4,256,746;

4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946;

4,315,929; 4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254;

4,362,663; and 4,371,533, each of which is incorporated herein by reference. Conjugates

containing maytansinoids, methods of making same, and their therapeutic use are disclosed, for

example, in U.S. Pat. Nos. 5,208,020; 5,416,064; 6,441,163 and European Patent EP 0 425 235

B1, the disclosures of which are hereby expressly incorporated by reference.

Additional toxins can be employed with a CAR, a T cell expressing a CAR, an antibody,

or antigen binding portion thereof. Exemplary toxins include Pseudomonas exotoxin (PE), ricin,

abrin, diphtheria toxin and subunits thereof, ribotoxin, ribonuclease, saporin, and calicheamicin,

as well as botulinum toxins A through F. These toxins are well known in the art and many are

readily available from commercial sources (for example, Sigma Chemical Company, St. Louis,

MO). Contemplated toxins also include variants of the toxins (see, for example, see, U.S. Patent

Nos. 5,079,163 and 4,689,401).

WO wo 2019/079249 PCT/US2018/056011

Saporin is a toxin derived from Saponaria officinalis that disrupts protein synthesis by

inactivating the 60S portion of the ribosomal complex (Stirpe et al., Bio/Technology, 10:405-412,

1992). However, the toxin has no mechanism for specific entry into cells, and therefore requires

conjugation to an antibody or antigen binding fragment that recognizes a cell-surface protein that

is internalized in order to be efficiently taken up by cells.

Diphtheria toxin is isolated from Corynebacterium diphtheriae. Typically, diphtheria toxin

for use in immunotoxins is mutated to reduce or to eliminate non-specific toxicity. A mutant

known as CRM107, which has full enzymatic activity but markedly reduced non-specific toxicity,

has been known since the 1970's (Laird and Groman, J. Virol. 19:220, 1976), and has been used

in human clinical trials. See, U.S. Patent No. 5,792,458 and U.S. Patent No. 5,208,021.

Ricin is the lectin RCA60 from Ricinus communis (Castor bean). For examples of ricin,

see, U.S. Patent No. 5,079,163 and U.S. Patent No. 4,689,401. Ricinus communis agglutinin

(RCA) occurs in two forms designated RCA60 and RCA and RCA120 RCA according according to their to their molecular molecular weights weights of of

approximately 65 and 120 kD, respectively (Nicholson & Blaustein, J. Biochim. Biophys. Acta

266:543, 1972). The A chain is responsible for inactivating protein synthesis and killing cells.

The B chain binds ricin to cell-surface galactose residues and facilitates transport of the A chain

into the cytosol (Olsnes et al., Nature 249:627-631, 1974 and U.S. Patent No. 3,060,165).

Ribonucleases have also been conjugated to targeting molecules for use as immunotoxins

(see (see Suzuki Suzukietet al., Nat. al., Biotech. Nat. 17:265-70, Biotech. 1999). 1999). 17:265-70, Exemplary ribotoxins Exemplary such as a-sarcin ribotoxins such asand-sarcin and

restrictocin are discussed in, for example Rathore et al., Gene 190:31-5, 1997; and Goyal and

Batra, Biochem. 345 Pt 2:247-54, 2000. Calicheamicins were first isolated from Micromonospora

echinospora and are members of the enediyne antitumor antibiotic family that cause double strand

breaks in DNA that lead to apoptosis (see, for example Lee et al., J. Antibiot. 42:1070-87,1989).

The drug is the toxic moiety of an immunotoxin in clinical trials (see, for example, Gillespie et al.,

Ann. Oncol. 11:735-41, 2000).

Abrin includes toxic lectins from Abrus precatorius. The toxic principles, abrin a, b, c,

and d, have a molecular weight of from about 63 and 67 kD and are composed of two disulfide-

linked polypeptide chains A and B. The A chain inhibits protein synthesis; the B chain (abrin-b)

binds to D-galactose residues (see, Funatsu et al., Agr. Biol. Chem. 52:1095, 1988; and Olsnes,

Methods Enzymol. 50:330-335, 1978).

A CAR, a T cell expressing a CAR, monoclonal antibodies, antigen binding fragments

thereof, specific for one or more of the antigens disclosed herein, can also be conjugated with a

detectable marker; for example, a detectable marker capable of detection by ELISA,

spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as

WO wo 2019/079249 PCT/US2018/056011

computed tomography (CT), computed axial tomography (CAT) scans, magnetic resonance

imaging (MRI), nuclear magnetic resonance imaging NMRI), magnetic resonance tomography

(MTR), ultrasound, fiberoptic examination, and laparoscopic examination). Specific, non-limiting

examples of detectable markers include fluorophores, chemiluminescent agents, enzymatic

linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic

iron oxide nanocrystals for detection by MRI). For example, useful detectable markers include

fluorescent compounds, including fluorescein, fluorescein isothiocyanate, rhodamine, 5-

dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin, lanthanide phosphors and the like.

Bioluminescent markers are also of use, such as luciferase, Green fluorescent protein (GFP),

Yellow fluorescent protein (YFP). A CAR, a T cell expressing a CAR, an antibody, or antigen

binding portion thereof, can also be conjugated with enzymes that are useful for detection, such as

horseradish peroxidase, B-galactosidase, ß-galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the

like. When a CAR, a T cell expressing a CAR, an antibody, or antigen binding portion thereof, is

conjugated conjugated with with aa detectable detectable enzyme, enzyme, it it can can be be detected detected by by adding adding additional additional reagents reagents that that the the

enzyme uses to produce a reaction product that can be discerned. For example, when the agent

horseradish peroxidase is present the addition of hydrogen peroxide and diaminobenzidine leads

to a colored reaction product, which is visually detectable. A CAR, a T cell expressing a CAR, an

antibody, or antigen binding portion thereof, may also be conjugated with biotin, and detected

through indirect measurement of avidin or streptavidin binding. It should be noted that the avidin

itself can be conjugated with an enzyme or a fluorescent label.

A CAR, a T cell expressing a CAR, an antibody, or antigen binding portion thereof, may

be conjugated with a paramagnetic agent, such as gadolinium. Paramagnetic agents such as

superparamagnetic iron oxide are also of use as labels. Antibodies can also be conjugated with

lanthanides (such as europium and dysprosium), and manganese. An antibody or antigen binding

fragment may also be labeled with a predetermined polypeptide epitopes recognized by a

secondary reporter (such as leucine zipper pair sequences, binding sites for secondary antibodies,

metal binding domains, epitope tags).

A CAR, a T cell expressing a CAR, an antibody, or antigen binding portion thereof, can

also be conjugated with a radiolabeled amino acid. The radiolabel may be used for both

diagnostic and therapeutic purposes. For instance, the radiolabel may be used to detect one or

more of the antigens disclosed herein and antigen expressing cells by x-ray, emission spectra, or

other diagnostic techniques. Further, the radiolabel may be used therapeutically as a toxin for

treatment of tumors in a subject, for example for treatment of a neuroblastoma. Examples of

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WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

labels for polypeptides include, but are not limited to, the following radioisotopes or

radionucleotides: radionucleotides: 3H, ³H, 14C,¹C, 15N,¹N, S, 90Y, Tc, Tc, ³S, Y, Superscript(1)In, ¹¹¹In, ¹²I, 1251, ¹³¹I. 1311.

Means of detecting such detectable markers are well known to those of skill in the art.

Thus, for example, radiolabels may be detected using photographic film or scintillation counters,

fluorescent markers may be detected using a photodetector to detect emitted illumination.

Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting

the reaction product produced by the action of the enzyme on the substrate, and colorimetric

labels are detected by simply visualizing the colored label.

D. Nucleotides, Expression, Vectors, and Host Cells

Further provided by an embodiment of the invention is a nucleic acid comprising a

nucleotide sequence encoding any of the CARs, an antibody, or antigen binding portion thereof,

described herein (including functional portions and functional variants thereof). The nucleic acids

of the invention may comprise a nucleotide sequence encoding any of the leader sequences,

antigen binding domains, transmembrane domains, and/or intracellular T cell signaling domains

described herein.

In some embodiments, the nucleotide sequence may be codon-modified. Without being

bound to a particular theory, it is believed that codon optimization of the nucleotide sequence

increases the translation efficiency of the mRNA transcripts. Codon optimization of the

nucleotide sequence may involve substituting a native codon for another codon that encodes the

same amino acid, but can be translated by tRNA that is more readily available within a cell, thus

increasing translation efficiency. Optimization of the nucleotide sequence may also reduce

secondary mRNA structures that would interfere with translation, thus increasing translation

efficiency.

In an embodiment of the invention, the nucleic acid may comprise a codon-modified

nucleotide sequence that encodes the antigen binding domain of the inventive CAR. In another

embodiment of the invention, the nucleic acid may comprise a codon-modified nucleotide

sequence that encodes any of the CARs described herein (including functional portions and

functional variants thereof).

"Nucleic acid" as used herein includes "polynucleotide," "oligonucleotide," and "nucleic

acid molecule," and generally means a polymer of DNA or RNA, which can be single-stranded or

double-stranded, synthesized or obtained (e.g., isolated and/or purified) from natural sources,

which can contain natural, non-natural or altered nucleotides, and which can contain a natural,

WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

non-natural or altered internucleotide linkage, such as a phosphoroamidate linkage or a

phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an

unmodified oligonucleotide. In some embodiments, the nucleic acid does not comprise any

insertions, deletions, inversions, and/or substitutions. However, it may be suitable in some

instances, as discussed herein, for the nucleic acid to comprise one or more insertions, deletions,

inversions, and/or substitutions.

A recombinant nucleic acid may be one that has a sequence that is not naturally occurring

or has a sequence that is made by an artificial combination of two otherwise separated segments

of sequence. This artificial combination is often accomplished by chemical synthesis or, more

commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic

engineering techniques, such as those described in Sambrook et al., supra. The nucleic acids can

be constructed based on chemical synthesis and/or enzymatic ligation reactions using procedures

known in the art. See, for example, Sambrook et al., supra, and Ausubel et al., supra. For

example, a nucleic acid can be chemically synthesized using naturally occurring nucleotides or

variously modified nucleotides designed to increase the biological stability of the molecules or to

increase the physical stability of the duplex formed upon hybridization (e.g., phosphorothioate

derivatives and acridine substituted nucleotides). Examples of modified nucleotides that can be

used to generate the nucleic acids include, but are not limited to, 5-fluorouracil, 5-bromouracil, 5-

chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)

uracil, 5-carboxymethylaminomethy1-2-thiouridine uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, 5-carboxymethylaminomethyluracil,

dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -

methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-

methylcytosine, N6-substituted adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-

methoxyaminomethy1-2-thiouracil methoxyaminomethyl-2-thiouracil,beta-D-mannosylqueosine, beta-D-mannosylqueosine,5'-methoxycarboxymethyluracil, 5'-methoxycarboxymethyluracil,5- 5-

methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine,

pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-

methyluracil, uracil-5-oxyacetic acid methylester, 3- (3-amino-3-N-2-carboxypropyl) uracil, and

2,6-diaminopurine. Alternatively, one or more of the nucleic acids of the invention can be

purchased from companies, such as Integrated DNA Technologies (Coralville, IA, USA).

The nucleic acid can comprise any isolated or purified nucleotide sequence which encodes

any of the CARs or functional portions or functional variants thereof. Alternatively, the

nucleotide sequence can comprise a nucleotide sequence which is degenerate to any of the

sequences or a combination of degenerate sequences.

WO wo 2019/079249 PCT/US2018/056011

An embodiment also provides an isolated or purified nucleic acid comprising a nucleotide

sequence which is complementary to the nucleotide sequence of any of the nucleic acids described

herein herein or ora anucleotide sequence nucleotide whichwhich sequence hybridizes under stringent hybridizes conditionsconditions under stringent to the nucleotide to the nucleotide

sequence of any of the nucleic acids described herein.

The nucleotide sequence which hybridizes under stringent conditions may hybridize under

high stringency conditions. By "high stringency conditions" is meant that the nucleotide sequence

specifically hybridizes to a target sequence (the nucleotide sequence of any of the nucleic acids

described herein) in an amount that is detectably stronger than non-specific hybridization. High

stringency conditions include conditions which would distinguish a polynucleotide with an exact

complementary sequence, or one containing only a few scattered mismatches from a random

sequence that happened to have a few small regions (e.g., 3-10 bases) that matched the nucleotide

sequence. Such small regions of complementarity are more easily melted than a full-length

complement of 14-17 or more bases, and high stringency hybridization makes them easily

distinguishable. Relatively high stringency conditions would include, for example, low salt and/or

high temperature conditions, such as provided by about 0.02-0.1 M NaCl or the equivalent, at

temperatures of about 50-70 °C. Such high stringency conditions tolerate little, if any, mismatch

between the nucleotide sequence and the template or target strand, and are particularly suitable for

detecting expression of any of the inventive CARs. It is generally appreciated that conditions can

be rendered more stringent by the addition of increasing amounts of formamide.

Also provided is a nucleic acid comprising a nucleotide sequence that is at least about 70%

or more, e.g., about 80%, about 90%, about 91%, 91 %,about about92%, 92%,about about93%, 93%,about about94%, 94%,about about95%, 95%,

about 96%, about 97%, about 98%, or about 99% identical to any of the nucleic acids described

herein.

In an embodiment, the nucleic acids can be incorporated into a recombinant expression

vector. In this regard, an embodiment provides recombinant expression vectors comprising any of

the nucleic acids. For purposes herein, the term "recombinant expression vector" means a

genetically-modified oligonucleotide or polynucleotide construct that permits the expression of an

mRNA, protein, polypeptide, or peptide by a host cell, when the construct comprises a nucleotide

sequence encoding the mRNA, protein, polypeptide, or peptide, and the vector is contacted with

the cell under conditions sufficient to have the mRNA, protein, polypeptide, or peptide expressed

within the cell. The vectors are not naturally-occurring as a whole.

However, parts of the vectors can be naturally-occurring. The recombinant expression

vectors can comprise any type of nucleotides, including, but not limited to DNA and RNA, which

can be single-stranded or double- stranded, synthesized or obtained in part from natural sources,

WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

and which can contain natural, non-natural or altered nucleotides. The recombinant expression

vectors can comprise naturally-occurring or non-naturally-occurring internucleotide linkages, or

both types of linkages. Preferably, the non-naturally occurring or altered nucleotides or

internucleotide internucleotide linkages linkages do do not not hinder hinder the the transcription transcription or or replication replication of of the the vector. vector.

In an embodiment, the recombinant expression vector can be any suitable recombinant

expression vector, and can be used to transform or transfect any suitable host cell. Suitable

vectors include those designed for propagation and expansion or for expression or both, such as

plasmids and viruses. The vector can be selected from the group consisting of the pUC series

(Fermentas Life Sciences, Glen Burnie, MD), the pBluescript series (Stratagene, LaJolla, CA), the

pET series (Novagen, Madison, WI), the pGEX series (Pharmacia Biotech, Uppsala, Sweden),

and the pEX series (Clontech, Palo Alto, CA).

Bacteriophage vectors, such as NÓTIO, AUTIO, NOTI AUTI 1, AZapII XZapII (Stratagene), EMBL4, and 2NMI ANMI

149, also can be used. Examples of plant expression vectors include pBIOI, pBIOl, pBI101.2, pBHO1 pBHOl 3, .3,

pBI121 and pBIN19 (Clontech). Examples of animal expression vectors include pEUK-Cl,

pMAM, and pMAMneo (Clontech). The recombinant expression vector may be a viral vector,

e.g., a retroviral vector or a lentiviral vector. A lentiviral vector is a vector derived from at least a

portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as

provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus

vectors that may be used in the clinic, include, for example, and not by way of limitation, the

LENTIVECTOR.RTM LENTIVECTOR.RTM.gene genedelivery deliverytechnology technologyfrom fromOxford OxfordBioMedica BioMedicaplc, plc,the the LENTIMAX.TM vector LENTIMAX.TM. vector system system from from Lentigen Lentigen and and the the like. like. Nonclinical Nonclinical types types of of lentiviral lentiviral

vectors are also available and would be known to one skilled in the art.

A number of transfection techniques are generally known in the art (see, e.g., Graham et

al., Virology, 52: 456-467 (1973); Sambrook et al., supra; Davis et al., Basic Methods in

Molecular Biology, Elsevier (1986); and Chu et al, Gene, 13: 97 (1981).

Transfection methods include calcium phosphate co-precipitation (see, e.g., Graham et al.,

supra), direct micro injection into cultured cells (see, e.g., Capecchi, Cell, 22: 479-488 (1980)),

electroporation (see, e.g., Shigekawa et al., BioTechniques, 6: 742-751 (1988)), liposome

mediated gene transfer (see, e.g., Mannino et al., BioTechniques, 6: 682-690 (1988)), lipid

mediated transduction (see, e.g., Feigner et al., Proc. Natl. Acad. Sci. USA, 84: 7413-7417

(1987)), and nucleic acid delivery using high velocity microprojectiles (see, e.g., Klein et al,

Nature, 327: 70-73 (1987)).

In an embodiment, the recombinant expression vectors can be prepared using standard

recombinant DNA techniques described in, for example, Sambrook et al., supra, and Ausubel et

WO wo 2019/079249 PCT/US2018/056011

al., supra. Constructs of expression vectors, which are circular or linear, can be prepared to

contain a replication system functional in a prokaryotic or eukaryotic host cell. Replication

systems can be derived, e.g., from ColEl, 2 u µ plasmid, a, 2, SV40, bovine papilloma virus, and the

like.

The recombinant expression vector may comprise regulatory sequences, such as transcription and translation initiation and termination codons, which are specific to the type of

host cell (e.g., bacterium, fungus, plant, or animal) into which the vector is to be introduced, as

appropriate, and taking into consideration whether the vector is DNA- or RNA-based. The

recombinant expression vector may comprise restriction sites to facilitate cloning.

The recombinant expression vector can include one or more marker genes, which allow for

selection of transformed or transfected host cells. Marker genes include biocide resistance, e.g.,

resistance to antibiotics, heavy metals, etc., complementation in an auxotrophic host to provide

prototrophy, and the like. Suitable marker genes for the inventive expression vectors include, for

instance, neomycin/G418 resistance genes, hygromycin resistance genes, histidinol resistance

genes, tetracycline resistance genes, and ampicillin resistance genes.

The recombinant expression vector can comprise a native or nonnative promoter operably

linked to the nucleotide sequence encoding the CAR (including functional portions and functional

variants thereof), or to the nucleotide sequence which is complementary to or which hybridizes to

the nucleotide sequence encoding the CAR. The selection of promoters, e.g., strong, weak,

inducible, tissue-specific and developmental-specific, is within the ordinary skill of the artisan.

Similarly, the combining of a nucleotide sequence with a promoter is also within the skill of the

artisan. The promoter can be a non-viral promoter or a viral promoter, e.g., a cytomegalovirus

(CMV) promoter, an SV40 promoter, an RSV promoter, or a promoter found in the long-terminal

repeat of the murine stem cell virus.

The recombinant expression vectors can be designed for either transient expression, for

stable expression, or for both. Also, the recombinant expression vectors can be made for

constitutive expression or for inducible expression.

Further, the recombinant expression vectors can be made to include a suicide gene. As

used herein, the term "suicide gene" refers to a gene that causes the cell expressing the suicide

gene to die. The suicide gene can be a gene that confers sensitivity to an agent, e.g., a drug, upon

the cell in which the gene is expressed, and causes the cell to die when the cell is contacted with

or exposed to the agent. Suicide genes are known in the art (see, for example, Suicide Gene

Therapy: Methods and Reviews, Springer, Caroline J. (Cancer Research UK Centre for Cancer

Therapeutics at the Institute of Cancer Research, Sutton, Surrey, UK), Humana Press, 2004) and

PCT/US2018/056011

include, for example, the Herpes Simplex Virus (HSV) thymidine kinase (TK) gene, cytosine

daminase, purine nucleoside phosphorylase, and nitroreductase.

An embodiment further provides a host cell comprising any of the recombinant expression

vectors described herein. As used herein, the term "host cell" refers to any type of cell that can

contain the inventive recombinant expression vector. The host cell can be a eukaryotic cell, e.g.,

plant, animal, fungi, or algae, or can be a prokaryotic cell, e.g., bacteria or protozoa. The host cell

can be a cultured cell or a primary cell, i.e., isolated directly from an organism, e.g., a human.

The host cell can be an adherent cell or a suspended cell, i.e., a cell that grows in suspension.

Suitable host cells are known in the art and include, for instance, DH5a E. coli cells, Chinese

hamster ovarian cells, monkey VERO cells, COS cells, HEK293 cells, and the like. For purposes

of amplifying or replicating the recombinant expression vector, the host cell may be a prokaryotic

cell, e.g., a DH5a cell. For purposes of producing a recombinant CAR, the host cell may be a

mammalian cell. The host cell may be a human cell. While the host cell can be of any cell type,

can originate from any type of tissue, and can be of any developmental stage, the host cell may be

a peripheral blood lymphocyte (PBL) or a peripheral blood mononuclear cell (PBMC). The host

cell may be a T cell.

For purposes herein, the T cell can be any T cell, such as a cultured T cell, e.g., a primary

T cell, or a T cell from a cultured T cell line, e.g., Jurkat, SupTI, SupTl, etc., or a T cell obtained from a

mammal. If obtained from a mammal, the T cell can be obtained from numerous sources,

including but not limited to blood, bone marrow, lymph node, the thymus, or other tissues or

fluids. T cells can also be enriched for or purified. The T cell may be a human T cell. The T cell

may be a T cell isolated from a human. The T cell can be any type of T cell and can be of any

developmental stage, including but not limited to, CD4+/CD8+ double positive T cells, CD4+

helper T cells, e.g., Th1 and Th2 cells, CD8+ T cells (e.g., cytotoxic T cells), tumor infiltrating

cells, memory T cells, memory stem cells, i.e. Tscm, naive T cells, and the like. The T cell may be

a CD8+ T cell or a CD4+ T cell.

In an embodiment, the CARs as described herein can be used in suitable non-T cells. Such

cells are those with an immune-effector function, such as, for example, NK cells, and T-like cells

generated from pluripotent stem cells.

Also provided by an embodiment is a population of cells comprising at least one host cell

described herein. The population of cells can be a heterogeneous population comprising the host

cell comprising any of the recombinant expression vectors described, in addition to at least one

other cell, e.g., a host cell (e.g., a T cell), which does not comprise any of the recombinant

expression vectors, or a cell other than a T cell, e.g., a B cell, a macrophage, a neutrophil, an

WO wo 2019/079249 PCT/US2018/056011

erythrocyte, a hepatocyte, an endothelial cell, an epithelial cell, a muscle cell, a brain cell, etc.

Alternatively, the population of cells can be a substantially homogeneous population, in which the

population comprises mainly host cells (e.g., consisting essentially of) comprising the

recombinant expression vector. The population also can be a clonal population of cells, in which

all cells of the population are clones of a single host cell comprising a recombinant expression

vector, such that all cells of the population comprise the recombinant expression vector. In one

embodiment of the invention, the population of cells is a clonal population comprising host cells

comprising a recombinant expression vector as described herein.

CARs (including functional portions and variants thereof), nucleic acids, recombinant

expression vectors, host cells (including populations thereof), and antibodies (including antigen

binding portions thereof), can be isolated and/or purified. For example, a purified (or isolated)

host cell preparation is one in which the host cell is more pure than cells in their natural

environment within the body. Such host cells may be produced, for example, by standard

purification techniques. In some embodiments, a preparation of a host cell is purified such that the

host cell represents at least about 50%, for example at least about 70%, of the total cell content of

the preparation. For example, the purity can be at least about 50%, can be greater than about

60%, about 70% or about 80%, or can be about 100%.

E. Methods of Treatment

It is contemplated that the CARs disclosed herein can be used in methods of treating or

preventing a disease in a mammal. In this regard, an embodiment provides a method of treating or

preventing cancer in a mammal, comprising administering to the mammal the CARs, the nucleic

acids, the recombinant expression vectors, the host cells, the population of cells, the antibodies

and/or the antigen binding portions thereof, and/or the pharmaceutical compositions in an amount

effective to treat or prevent cancer in the mammal.

An embodiment further comprises lymphodepleting the mammal prior to administering the

CARs disclosed herein. Examples of lymphodepletion include, but may not be limited to,

nonmyeloablative lymphodepleting chemotherapy, myeloablative lymphodepleting chemotherapy,

total body irradiation, etc.

For purposes of the methods, wherein host cells or populations of cells are administered,

the cells can be cells that are allogeneic or autologous to the mammal. Preferably, the cells are

autologous to the mammal. As used herein, allogeneic means any material derived from a

different animal of the same species as the individual to whom the material is introduced. Two or

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more individuals are said to be allogeneic to one another when the genes at one or more loci are

not identical. In some aspects, allogeneic material from individuals of the same species may be

sufficiently unlike genetically to interact antigenically. As used herein, "autologous" means any

material derived from the same individual to whom it is later to be re-introduced into the

individual.

The mammal referred to herein can be any mammal. As used herein, the term "mammal"

refers to any mammal, including, but not limited to, mammals of the order Rodentia, such as mice

and hamsters, and mammals of the order Logomorpha, such as rabbits. The mammals may be

from the order Carnivora, including Felines (cats) and Canines (dogs). The mammals may be

from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order

Perssodactyla, including Equines (horses). The mammals may be of the order Primates, Ceboids,

or Simoids (monkeys) or of the order Anthropoids (humans and apes). Preferably, the mammal is

a human.

With respect to the methods, the cancer can be any cancer, including any of ALL, AML,

alveolar rhabdomyosarcoma, bladder cancer (e.g., bladder carcinoma), bone cancer, brain cancer

(e.g., medulloblastoma), breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the

eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or

pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the

vulva, chronic lymphocytic leukemia (CLL), chronic myeloid cancer (CML), colon cancer,

esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, head and neck

cancer (e.g., head and neck squamous cell carcinoma), Hodgkin lymphoma, hypopharynx cancer,

kidney cancer, larynx cancer, leukemia, liquid tumors, liver cancer, lung cancer (e.g., non-small

cell lung carcinoma and lung adenocarcinoma), lymphoma, mesothelioma, mastocytoma,

melanoma, multiple myeloma, nasopharynx cancer, NHL, B-chronic lymphocytic leukemia, hairy

cell leukemia, Burkitt's lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and

mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, small

intestine cancer, soft tissue cancer, solid tumors, synovial sarcoma, gastric cancer, testicular

cancer, thyroid cancer, and ureter cancer.

The terms "treat," and "prevent" as well as words stemming therefrom, as used herein, do

not necessarily imply 100% or complete treatment or prevention. Rather, there are varying

degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a

potential benefit or therapeutic effect. In this respect, the methods can provide any amount or any

level of treatment or prevention of cancer in a mammal.

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Furthermore, the treatment or prevention provided by the method can include treatment or

prevention of one or more conditions or symptoms of the disease, e.g., cancer, being treated or

prevented. Also, for purposes herein, "prevention" can encompass delaying the onset of the

disease, or a symptom or condition thereof.

Another embodiment provides a method of detecting the presence of cancer in a mammal,

comprising: (a) contacting a sample comprising one or more cells from the mammal with the

CARs, the nucleic acids, the recombinant expression vectors, the host cells, the population of

cells, the antibodies, and/or the antigen binding portions thereof, or the pharmaceutical

compositions, thereby forming a complex, (b) and detecting the complex, wherein detection of the

complex is indicative of the presence of cancer in the mammal.

The sample may be obtained by any suitable method, e.g., biopsy or necropsy. A biopsy is

the removal of tissue and/or cells from an individual. Such removal may be to collect tissue and/or

cells from the individual in order to perform experimentation on the removed tissue and/or cells.

This experimentation may include experiments to determine if the individual has and/or is

suffering from a certain condition or disease-state. The condition or disease may be, e.g., cancer.

With respect to an embodiment of the method of detecting the presence of a proliferative

disorder, e.g., cancer, in a mammal, the sample comprising cells of the mammal can be a sample

comprising whole cells, lysates thereof, or a fraction of the whole cell lysates, e.g., a nuclear or

cytoplasmic fraction, a whole protein fraction, or a nucleic acid fraction. If the sample comprises

whole cells, the cells can be any cells of the mammal, e.g., the cells of any organ or tissue,

including blood cells or endothelial cells.

The contacting can take place in vitro or in vivo with respect to the mammal. Preferably,

the contacting is in vitro.

Also, detection of the complex can occur through any number of ways known in the art.

For instance, the CARs disclosed herein, polypeptides, proteins, nucleic acids, recombinant

expression vectors, host cells, populations of cells, or antibodies, or antigen binding portions

thereof, described herein, can be labeled with a detectable label such as, for instance, a

radioisotope, a fluorophore (e.g., fluorescein isothiocyanate (FITC), phycoerythrin (PE)), an

enzyme (e.g., alkaline phosphatase, horseradish peroxidase), and element particles (e.g., gold

particles) as disclosed supra.

Methods of testing a CAR for the ability to recognize target cells and for antigen

specificity are known in the art. For instance, Clay et al., J. Immunol, 163: 507-513 (1999),

teaches methods of measuring the release of cytokines (e.g., interferon-y, granulocyte/monocyte

colony stimulating factor (GM-CSF), tumor necrosis factor a (TNF-a) or interleukin 2 (IL-2)). In

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addition, CAR function can be evaluated by measurement of cellular cytotoxicity, as described in

Zhao et al, J. Immunol Immunol,, 174: 174: 4415-4423 4415-4423 (2005). (2005).

Another embodiment provides for the use of the CARs, nucleic acids, recombinant

expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof,

and/or pharmaceutical compositions of the invention, for the treatment or prevention of a

proliferative disorder, e.g., cancer, in a mammal. The cancer may be any of the cancers described

herein.

Any method of administration can be used for the disclosed therapeutic agents, including

local and systemic administration. For example topical, oral, intravascular such as intravenous,

intramuscular, intraperitoneal, intranasal, intradermal, intrathecal and subcutaneous administration

can be used. The particular mode of administration and the dosage regimen will be selected by

the attending clinician, taking into account the particulars of the case (for example the subject, the

disease, the disease state involved, and whether the treatment is prophylactic). In cases in which

more than one agent or composition is being administered, one or more routes of administration

may be used; for example, a chemotherapeutic agent may be administered orally and an antibody

or antigen binding fragment or conjugate or composition may be administered intravenously.

Methods of administration include injection for which the CAR, CAR T Cell, conjugates,

antibodies, antigen binding fragments, or compositions are provided in a nontoxic pharmaceutically acceptable carrier such as water, saline, Ringer's solution, dextrose solution, 5%

human serum albumin, fixed oils, ethyl oleate, or liposomes. In some embodiments, local

administration of the disclosed compounds can be used, for instance by applying the antibody or

antigen binding fragment to a region of tissue from which a tumor has been removed, or a region

suspected of being prone to tumor development. In some embodiments, sustained intra-tumoral

(or near-tumoral) release of the pharmaceutical preparation that includes a therapeutically

effective amount of the antibody or antigen binding fragment may be beneficial. In other

examples, the conjugate is applied as an eye drop topically to the cornea, or intravitreally into the

eye.

The disclosed therapeutic agents can be formulated in unit dosage form suitable for

individual administration of precise dosages. In addition, the disclosed therapeutic agents may be

administered in a single dose or in a multiple dose schedule. A multiple dose schedule is one in

which a primary course of treatment may be with more than one separate dose, for instance 1-10

doses, followed by other doses given at subsequent time intervals as needed to maintain or

reinforce the action of the compositions. Treatment can involve daily or multi-daily doses of

compound(s) over a period of a few days to months, or even years. Thus, the dosage regime will

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also, at least in part, be determined based on the particular needs of the subject to be treated and

will be dependent upon the judgment of the administering practitioner.

Typical dosages of the antibodies or conjugates can range from about 0.01 to about 30

mg/kg, such as from about 0.1 to about 10 mg/kg.

In particular examples, the subject is administered a therapeutic composition that includes

one or more of the conjugates, antibodies, compositions, CARs, CAR T cells or additional agents,

on a multiple daily dosing schedule, such as at least two consecutive days, 10 consecutive days,

and SO so forth, for example for a period of weeks, months, or years. In one example, the subject is

administered the conjugates, antibodies, compositions or additional agents for a period of at least

30 days, such as at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least

24 months, or at least 36 months.

In some embodiments, the disclosed methods include providing surgery, radiation therapy,

and/or chemotherapeutics to the subject in combination with a disclosed antibody, antigen binding

fragment, conjugate, CAR or T cell expressing a CAR (for example, sequentially, substantially

simultaneously, or simultaneously). Methods and therapeutic dosages of such agents and

treatments are known to those skilled in the art, and can be determined by a skilled clinician.

Preparation and dosing schedules for the additional agent may be used according to manufacturer's instructions or as determined empirically by the skilled practitioner. Preparation

and dosing schedules for such chemotherapy are also described in Chemotherapy Service, (1992)

Ed., M. C. Perry, Williams & Wilkins, Baltimore, Md.

In some embodiments, the combination therapy can include administration of a therapeutically effective amount of an additional cancer inhibitor to a subject. Non-limiting

examples of additional therapeutic agents that can be used with the combination therapy include

microtubule binding agents, DNA intercalators or cross-linkers, DNA synthesis inhibitors, DNA

and RNA transcription inhibitors, antibodies, enzymes, enzyme inhibitors, gene regulators, and

angiogenesis inhibitors. These agents (which are administered at a therapeutically effective

amount) and treatments can be used alone or in combination. For example, any suitable anti-

cancer or anti-angiogenic agent can be administered in combination with the CARS, CAR- T

cells, antibodies, antigen binding fragment, or conjugates disclosed herein. Methods and

therapeutic dosages of such agents are known to those skilled in the art, and can be determined by

a skilled clinician.

Additional chemotherapeutic agents include, but are not limited to alkylating agents, such

as nitrogen mustards (for example, chlorambucil, chlormethine, cyclophosphamide, ifosfamide,

and melphalan), nitrosoureas (for example, carmustine, fotemustine, lomustine, and streptozocin),

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platinum compounds (for example, carboplatin, cisplatin, oxaliplatin, and BBR3464), busulfan,

dacarbazine, mechlorethamine, procarbazine, temozolomide, thiotepa, and uramustine;

antimetabolites, such as folic acid (for example, methotrexate, pemetrexed, and raltitrexed),

purine (for example, cladribine, clofarabine, fludarabine, mercaptopurine, and tioguanine),

pyrimidine (for example, capecitabine), cytarabine, fluorouracil, and gemcitabine; plant alkaloids,

such as podophyllum (for example, etoposide, and teniposide), taxane (for example, docetaxel and

paclitaxel), vinca (for example, vinblastine, vincristine, vindesine, and vinorelbine);

cytotoxic/antitumor antibiotics, such as anthracycline family members (for example,

daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin), bleomycin,

rifampicin, hydroxyurea, and mitomycin; topoisomerase inhibitors, such as topotecan and

irinotecan; monoclonal antibodies, such as alemtuzumab, bevacizumab, cetuximab, gemtuzumab,

rituximab, panitumumab, pertuzumab, and trastuzumab; photosensitizers, such as aminolevulinic

acid, methyl aminolevulinate, porfimer sodium, and verteporfin; and other agents , such as

alitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide, asparaginase, axitinib,

bexarotene, bevacizumab, bortezomib, celecoxib, denileukin diftitox, erlotinib, estramustine,

gefitinib, hydroxycarbamide, imatinib, lapatinib, pazopanib, pentostatin, masoprocol, mitotane,

pegaspargase, tamoxifen, sorafenib, sunitinib, vemurafinib, vandetanib, and tretinoin. Selection

and therapeutic dosages of such agents are known to those skilled in the art, and can be

determined by a skilled clinician.

The combination therapy may provide synergy and prove synergistic, that is, the effect

achieved when the active ingredients used together is greater than the sum of the effects that

results from using the compounds separately. A synergistic effect may be attained when the

active ingredients are: (1) co-formulated and administered or delivered simultaneously in a

combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate

formulations; or (3) by some other regimen. When delivered in alternation, a synergistic effect

may be attained when the compounds are administered or delivered sequentially, for example by

different injections in separate syringes. In general, during alternation, an effective dosage of

each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy,

effective dosages of two or more active ingredients are administered together.

one embodiment, In one embodiment,an an effective effective amount amount of an of an antibody antibody or antigen or antigen bindingthat binding fragment fragment that

specifically binds to one or more of the antigens disclosed herein or a conjugate thereof is

administered to a subject having a tumor following anti-cancer treatment. After a sufficient

amount of time has elapsed to allow for the administered antibody or antigen binding fragment or

conjugate to form an immune complex with the antigen expressed on the respective cancer cell,

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the immune complex is detected. The presence (or absence) of the immune complex indicates the

effectiveness of the treatment. For example, an increase in the immune complex compared to a

control taken prior to the treatment indicates that the treatment is not effective, whereas a decrease

in the immune complex compared to a control taken prior to the treatment indicates that the

treatment is effective.

F. Biopharmaceutical Compositions

Biopharmaceutical or biologics compositions (hereinafter, "compositions") are provided

herein for use in gene therapy, immunotherapy and/or cell therapy that include one or more of the

disclosed CARs, or T cells expressing a CAR, antibodies, antigen binding fragments, conjugates,

CARs, or T cells expressing a CAR that specifically bind to one or more antigens disclosed

herein, in a carrier (such as a pharmaceutically acceptable carrier). The compositions can be

prepared in unit dosage forms for administration to a subject. The amount and timing of of

administration are at the discretion of the treating clinician to achieve the desired outcome. The

compositions can be formulated for systemic (such as intravenous) or local (such as intra-tumor)

administration. In one example, a disclosed CARs, or T cells expressing a CAR, antibody,

antigen binding fragment, conjugate, is formulated for parenteral administration, such as

intravenous administration. Compositions including a CAR, or T cell expressing a CAR, a

conjugate, antibody or antigen binding fragment as disclosed herein are of use, for example, for

the treatment and detection of a tumor, for example, and not by way of limitation, a

neuroblastoma. In some examples, the compositions are useful for the treatment or detection of a

carcinoma. The compositions including a CAR, or T cell expressing a CAR, a conjugate,

antibody or antigen binding fragment as disclosed herein are also of use, for example, for the

detection of pathological angiogenesis.

The compositions for administration can include a solution of the CAR, or T cell

expressing a CAR, conjugate, antibody or antigen binding fragment dissolved in a pharmaceutically acceptable carrier, such as an aqueous carrier. A variety of aqueous carriers can

be used, for example, buffered saline and the like. These solutions are sterile and generally free of

undesirable matter. These compositions may be sterilized by conventional, well known

sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary

substances as required to approximate physiological conditions such as pH adjusting and

buffering agents, toxicity adjusting agents, adjuvant agents, and the like, for example, sodium

acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The

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concentration of a CAR, or T cell expressing a CAR, antibody or antigen binding fragment or

conjugate in these formulations can vary widely, and will be selected primarily based on fluid

volumes, viscosities, body weight and the like in accordance with the particular mode of

administration selected and the subject's needs. Actual methods of preparing such dosage forms

for use in in gene therapy, immunotherapy and/or cell therapy are known, or will be apparent, to

those skilled in the art.

A typical composition for intravenous administration includes about 0.01 to about 30

mg/kg of antibody or antigen binding fragment or conjugate per subject per day (or the

corresponding dose of a CAR, or T cell expressing a CAR, conjugate including the antibody or

antigen binding fragment). Actual methods for preparing administrable compositions will be

known or apparent to those skilled in the art and are described in more detail in such publications

as Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, PA (1995).

A CAR, or T cell expressing a CAR, antibodies, antigen binding fragments, or conjugates

may be provided in lyophilized form and rehydrated with sterile water before administration,

although they are also provided in sterile solutions of known concentration. The CARs, or T cells

expressing a CAR, antibody or antigen binding fragment or conjugate solution is then added to an

infusion bag containing 0.9% sodium chloride, USP, and in some cases administered at a dosage

of from 0.5 to 15 mg/kg of body weight. Considerable experience is available in the art in the

administration of antibody or antigen binding fragment and conjugate drugs; for example,

antibody drugs have been marketed in the U.S. since the approval of RITUXAN RITUXAN®in in1997. 1997.A ACAR, CAR,

or T cell expressing a CAR, antibodies, antigen binding fragments and conjugates thereof can be

administered by slow infusion, rather than in an intravenous push or bolus. In one example, a

higher loading dose is administered, with subsequent, maintenance doses being administered at a

lower level. For example, an initial loading dose of 4 mg/kg antibody or antigen binding fragment

(or the corresponding dose of a conjugate including the antibody or antigen binding fragment)

may be infused over a period of some 90 minutes, followed by weekly maintenance doses for 4-8

weeks of 2 mg/kg infused over a 30 minute period if the previous dose was well tolerated.

Controlled release parenteral formulations can be made as implants, oily injections, or as

particulate systems. For a broad overview of protein delivery systems see, Banga, A.J.,

Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Technomic

Publishing Company, Inc., Lancaster, PA, (1995). Particulate systems include microspheres,

microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles. Microcapsules

contain the therapeutic protein, such as a cytotoxin or a drug, as a central core. In microspheres,

the therapeutic is dispersed throughout the particle. Particles, microspheres, and microcapsules

PCT/US2018/056011

smaller than about 1 um µm are generally referred to as nanoparticles, nanospheres, and

nanocapsules, respectively. Capillaries have a diameter of approximately 5 um µm SO so that only

nanoparticles are administered intravenously. Microparticles are typically around 100 um µm in

diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, J.,

Colloidal Drug Delivery Systems, J. Kreuter, ed., Marcel Dekker, Inc., New York, NY, pp. 219-

342 (1994); and Tice & Tabibi, Treatise on Controlled Drug Delivery, A. Kydonieus, ed., Marcel

Dekker, Inc. New York, NY, pp. 315-339, (1992).

Polymers can be used for ion-controlled release of the CARs, or T cells expressing a CAR,

antibody or antigen binding fragment or conjugate compositions disclosed herein. Various

degradable and nondegradable polymeric matrices for use in controlled drug delivery are known

in the art (Langer, Accounts Chem. Res. 26:537-542, 1993). For example, the block copolymer,

polaxamer 407, exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel

at body temperature. It has been shown to be an effective vehicle for formulation and sustained

delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res. 9:425-434, 1992;

and Pec et al., J. Parent. Sci. Tech. 44(2):58-65, 1990). Alternatively, hydroxyapatite has been

used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112:215-224,

1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of

the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems, Technomic

Publishing Co., Inc., Lancaster, PA (1993)). Numerous additional systems for controlled delivery

of therapeutic proteins are known (see U.S. Patent No. 5,055,303; U.S. Patent No. 5,188,837; U.S.

Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; U.S. Patent No.

4,957,735; U.S. Patent No. 5,019,369; U.S. Patent No. 5,055,303; U.S. Patent No. 5,514,670; U.S.

Patent No. 5,413,797; U.S. Patent No. 5,268,164; U.S. Patent No. 5,004,697; U.S. Patent No.

4,902,505; U.S. Patent No. 5,506,206; U.S. Patent No. 5,271,961; U.S. Patent No. 5,254,342 and

U.S. Patent No. 5,534,496).

G. Kits

In one aspect, kits employing the CARs disclosed herein are also provided. For example,

kits for treating a tumor in a subject, or making a CAR T cell that expresses one or more of the

CARs disclosed herein. The kits will typically include a disclosed antibody, antigen binding

fragment, conjugate, nucleic acid molecule, CAR or T cell expressing a CAR as disclosed herein.

PCT/US2018/056011

More than one of the disclosed antibodies, antigen binding fragments, conjugates, nucleic acid

molecules, CARs or T cells expressing a CAR can be included in the kit.

The kit can include a container and a label or package insert on or associated with the

container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers

may be formed from a variety of materials such as glass or plastic. The container typically holds a

composition including one or more of the disclosed antibodies, antigen binding fragments,

conjugates, nucleic acid molecules, CARs or T cells expressing a CAR. In several embodiments

the container may have a sterile access port (for example the container may be an intravenous

solution bag or a vial having a stopper pierceable by a hypodermic injection needle). A label or

package insert indicates that the composition is used for treating the particular condition.

The label or package insert typically will further include instructions for use of a disclosed

antibodies, antigen binding fragments, conjugates, nucleic acid molecules, CARs or T cells

expressing a CAR, for example, in a method of treating or preventing a tumor or of making a

CAR T cell. The package insert typically includes instructions customarily included in

commercial packages of therapeutic products that contain information about the indications,

usage, dosage, administration, contraindications and/or warnings concerning the use of such

therapeutic products. The instructional materials may be written, in an electronic form (such as a a

computer diskette or compact disk) or may be visual (such as video files). The kits may also

include additional components to facilitate the particular application for which the kit is designed.

Thus, for example, the kit may additionally contain means of detecting a label (such as enzyme

substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels

such as a secondary antibody, or the like). The kits may additionally include buffers and other

reagents routinely used for the practice of a particular method. Such kits and appropriate contents

are well known to those of skill in the art.

EXAMPLES

This invention is further illustrated by the following examples, which are not to be

construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be

clearly understood that resort may be had to various other embodiments, modifications, and

equivalents thereof which, after reading the description herein, may suggest themselves to those

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skilled in the art without departing from the spirit of the present invention and/or the scope of the

appended claims.

EXAMPLE 1

Isolation of CD22-Specific Antibodies from a Fully Human Phage and Yeast-Displayed ScFv

library

MATERIALS AND METHODS:

a) Production of Human ScFv and CD22-Specific Antibodies

A naive naïve human ScFv (recombinant single chain fragment variable of immunoglobulin)

phage display library (approximate diversity, 1010 unique specificities), 10¹ unique specificities), constructed constructed from from

peripheral blood B cells of 50 healthy donors (Z. Y. Zhu and D. S. Dimitrov, unpublished data),

were used for selection of ScFvs for recombinant human CD19 protein (Miltenyi Biotec,

unpublished). Amplified libraries of 1012 10¹² phage-displayed ScFv were incubated with 5, 3, and 1,

ug µg of coated CD22 in a 5x100-ul 5x100-µl volume, distributed equally in 5 wells of a 96-well plate for 2 h

at room temperature during the first, second and third rounds of biopanning, respectively. After

each round of incubation the wells were washed 5 times for the first round and 10 times for the

later rounds with phosphate-buffered saline containing 0.05% Tween 20 (PBST) to remove

nonspecifically bound phage, the bound phage were mixed with TG1 competent cells for 1 hour at

37°, 37°C,and andthe thephage phagewas wasamplified amplifiedfrom fromthe theinfected infectedcells cellsand andused usedin inthe thenext nextround round of of

biopanning. After the third round of biopanning, 380 clones were randomly picked from the

infected TG1 cells and each inoculated into 150 ul µl 2YT medium containing 100 ug/ml µg/ml

carbenicillin and 0.2% glucose in 96-well plates by using the automated BioRobotics BioPick

colony picking system (Genomic Solutions, Ann Arbor, MI). After the bacterial cultures reached

an optical density at 600 nm (OD600) of 0.5, helper phage M13K07 at a multiplicity of infection

(MOI) of 10 and kanamycin at 50 ug/ml µg/ml (final concentration) were added to the medium, and the

plates were further incubated at 30°C overnight in a shaker at 250 rpm. The phage supernatants

were mixed with 3% nonfat milk in PBS at a 4:1 volume ratio and used for enzyme-linked

immunosorbent assay (ELISA) to identify clones of phage displaying ScFvs or VHs with high

CD22 binding affinity. The supernatants were incubated for 2 h at room temperature with

recombinant human CD22 coated at 50 ng per well in 96-well plates and washed five times with

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PBST, (after overnight incubation at 4°C it was blocked with 3% nonfat milk in PBS and washed

three times with PBS containing 0.05% Tween 20.) CD22-bound phage were detected using

horseradish peroxidase-conjugated goat anti-M13 antibody. After incubation with the antibody,

the nonspecifically bound antibody was removed by washing wells, and the 3,3,'5,5'-

tetramethylbenzidine (TMB) substrate was added, and solution absorbance at 450 nm (A450)

measured. Clones that bound to CD22 with A450 of >1.0 were selected for further characterization.

b) Expression and purification of selected soluble ScFvs

The VH and VL of the selected clones were DNA sequenced, and the ScFvs encoded by

clones with unique sequences were expressed and purified as described below. Plasmids

extracted from these clones were used for transformation of HB2151 cells. A single colony was

picked from the plate containing freshly transformed cells, inoculated into 200 ml 2YT medium

containing 100 ug/ml µg/ml ampicillin and 0.2% glucose, and incubated at 37°C with shaking at 250

rpm. When the culture OD at 600 nm reached 0.90, isopropy1-B-d-thiogalactopyranoside isopropyl-ß-d-thiogalactopyranoside at a 0.5

mM final concentration was added, and the culture was further incubated overnight at 30°C. The

bacterial pellet was collected after centrifugation at 8,000 X g for 20 min and resuspended in PBS

buffer containing 0.5 mU polymixin B (Sigma-Aldrich, St. Louis, MO). After 30 min incubation

with rotation at 50 rpm at room temperature, the resuspended pellet was centrifuged at 25,000 X g

for 25 min at 4°C, and the supernatant was used for ScFv purification using the Ni-NTA resin

following vendor protocol (Qiagen).

c) ELISA binding assay

For ELISA analysis 50 ul µl of the diluted recombinant human CD22 in PBS at 2ug/ml was

coated in a 96-well plate at 4°C overnight. Purified ScFv with His and Flag tags were serially

diluted and added into the target protein coated wells wells.After Afterwashing, washing,a a1:3000 1:3000diluted dilutedHRP HRP

conjugated anti-Flag antibody was added for 1 hr at RT. After washing, 3, 3, 5, 5' 5'--

Tetramethylbenzidine (TMB) substrate was added, 1N H2SO4 was added to stop the reaction after

incubation at room temperature for 10 minutes, and the O.D. was read at 450 nm to quantify the

relative ability of ScFv to bind CD22.

d) Yeast display of scFv library

PCT/US2018/056011

The same ScFv starting material as for phage display was also incorporated into a yeast

ScFv display system. To supplement phage-based scFv analysis, yeast libraries expressing the

human scFv library were also screened. To enrich the yeast expressing scFvs that bind to both the

recombinant CD22-Fc and the CD19 expressed on the cell surface of the CHOK1 cells, cell

panning on CHOK1 transfected with CD222 cells was CD22 cells was performed. performed. For For the the first first round round of of panning panning

on the cell surface, two days prior to panning, the CHOK1-CD22 cells were seeded into 6-well

plates and grown to 50% confluency in F12 K medium. 5 X x 107 yeast cells 10 yeast cells were were then then washed washed 2x 2x

with PBSA buffer and resuspended into 3mL F12 K medium, and then gently added dropwise to

the CHOK1-CD22 cells. After rocking gently on ice for 2 hours, the CHOK1-CD22 cells were

then washed 3 times with ice-cold PBSA to remove the yeast cells that did not bind to the

CHOK1-CD22, and .05% Trypsin-EDTA (Gibco) was then used to dissociate the CHOK1-CD22

cells and bound yeast cells from the plate. The cell mix containing both the yeast and CHOK1

cells were then inoculated into 10 mL SDCAA medium and amplified overnight at 30°C and then

induced in SGCAA medium at 30°C for 16 hours. For the second round of cell panning, a similar

protocol as above was performed, but more stringent wash conditions were used. This method of

panning yielded the 16P, 24P, 25P, 11S and 12S binders. Binder sequences were incorporated

into CART constructs as described in Example 2, infra, in a series of in vitro CART functional

assays. Characterization of these binders from phage display in CART format revealed that only

16P binder had specific tumor-lytic activity in vitro, but it was low as compared to CAR positive

control. Further, when 16P-based CART cells were tested in in vivo xenograft model, its

antitumor function was very weak (Example 2, infra). Taken together, these results indicated that

affinity maturation of anti-CD22 ScFv binders was required, as the biological characteristics of

the CAR created from this binder set were still not optimal.

To increase the affinity of 16P, a yeast-display mutant scFv library was created by using

error-prone PCR to create random point mutations in scFv gene sequences. After electroporation,

the resulting mutant library was then grown overnight at 30°C for 16 hours in SDCAA medium

and then switched into SGCAA medium at 30°C for another 16 hours. The mutant library was

then sorted through MACS (immunomagentic column, Miltenyi Biotec) with CD22-Fc as the

capture antigen to downsize the library and to increase the population of mutants that could bind

to CD22-Fc. The strongest binders were then selected by double staining the pools with Anti-c-

Myc-Alexa 488 and CD19-Fc/Anti-Hu-Fc and selecting for the binders that had the highest

binding affinities as well as c-Myc expression levels. This process was then repeated two more

times, until flow cytometry of yeast particles with fluorescently tagged antigen yielded average

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binding affinities of the mutant pools that were increased over the starting construct. Biniding Binidng

affinities were estimated by flow cytometry of yeast pools using decreasing amounts of labeled

CD22. This process resulted in an increase of EC50 (Effective concentration for 50% binding of

labeled CD19 on yeast displaying ScFv) for 16P of 0.5 ug/ml to an affinity of <0.01 ug/ml for the

affinity matured binders (16P1, 16P2, 16P3, 16P3v2, 16P6, 16P8, 16P10, 16P13, 16P15, 16P16,

16P17, 16P20, 16P20v2).

RESULTS:

Due to the unique challenges of CD222 structure,phage CD22 structure, phagedisplay displaycandidates candidatesdid didnot notyield yield

sufficient functional CAR constructs with high biological activity and specificity. Thus, ScFv for

biologically active and highly specific binders were generated by yeast display. Based upon flow

cytometry analysis of yeast-displayed ScFv, thirteen ScFv clones specific for recombinant human

CD22 were identified and labeled as human anti-CD22 ScFv binders 16P (LTG2202, founder

clone, EC50 of 0.5 ug/ml), and the following affinity matured binders (EC50 <0.01 ug/ml): 16P1,

16P2, 16P3, 16P3v2, 16P6, 16P8, 16P10, 16P13, 16P15, 16P17, 16P20, and 16P20v2

respectively. The generation of CARs expressing the LTG2203, LTG2205, LTG2206, LTG2207,

LTG2208, LTG2209, LTG2210, LTG2216, LTG2217, LTG2218, LTG2219, and LTG2220 human anti-CD22 binders is outlined in Example 2, infra.

EXAMPLE 2

CARs Expressing Anti-CD22 Fully Human Binding sequences.

Homo sapiens CD22 (SIGLEC-2, Leul4) Leu14) is a well-investigated cell surface glycoprotein

expressed on B cell leukemias and lymphomas. At least two anti-CD22 antibody drug

(Inotuzumab Ozogamicin) or immunotoxin conjugates (Moxetumomab Pasudotox) have been the

subject of clinical trials (NCT02981628, NCT00659425). These approaches have had some

success, and are still being investigated, for example in combination with other chemotherapeutic

agents (Muller F, Stookey S, Cunningham T, Pastan I, 2017, Paclitaxel synergizes with exposure

tume adjusted CD22-targeted immunotoxins against B-cell malignancies, Oncotarget 8:30644-

30655). However, given the current advances with T-cell based therapy with CD19 CARs, the best

approach to targeting CD22-expressing malignancies may be cell-based immunotherapy. Therapy

featuring the m971-based anti-CD22 CAR is currently undergoing clinical trial at the National

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Cancer Institute (NCT02315612, P.I.: Terry Fry, M.D.), although results have not yet been

published. The CAR constructs presented here are an innovative new approach to creating and

implementing new CD22 binding moieties derived from human sequences and given the range of

cytotoxicity and cytokine-producing capabilities of each construct, very different activity profiles

may be seen in vivo.

The novel anti-CD22 CAR-T constructs described here have high levels of cell surface

expression in primary human T cells and specific and potent cytotoxic and cytokine functions

against CD22-positive tumor cells. CD22 CARs were designed using CD22 binding sequences

derived from ScFv candidates initially identified by phage display, as in Example 1, and for

characterization were cloned into lentiviral expression vectors that contained selected structural

and signaling domains under the control of the EFla promoter and tested in vitro for transduction

efficiency, killing function and cytokine production in both model cell lines and primary human T

cells. Table 1 summarizes the nomenclature used. CAR Construct LTG1538, an anti-CD19 CAR,

serves as a positive control and a comparator. The m971 CAR LTG2200, is used as an anti-CD22

CAR positive control.

Table 1 - Construct LTG numbers and corresponding ScFv binder designations used in the design of fully human CD22 CARs

CAR Construct LTG# ScFv Binder Designation CAR Construct Description

2200 m971 CAR22 positive control

2202 16P New construct

2246 24P New construct

2247 25P New construct

2248 11S 11S New construct

2249 12S New construct

2203 16P3 New construct

2204 16P16 New construct

2205 16P20 New construct

2206 16P2 New construct

2207 16P6 New construct

2208 16P10 New construct

2209 16P17 New construct

2210 16P20v2 New construct

2216 16P1 New construct

2217 16P3v2 New construct

2218 16P8 New construct

2219 16P13 New construct

2220 16P15 New construct

1538 FMC63 CD19-specific CAR

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UTD N/A Untransduced T cells

MATERIALS AND METHODS:

(a) Cell Lines

The Burkitt lymphoma cell line Raji, and the chronic myelogenous leukemia line

K562 were purchased from American Tissue Culture Collection (ATCC, Manassass, VA).

The REH and NALM-6 leukemia lines were purchased from DSMZ (Leibniz Institute DSMZ,

Braunschwieg, Germany). Cells were cultured in RPMI-1640 medium supplemented with

10% heat-inactivated fetal bovine serum (FBS, Hyclone, Logan, UT) and 2mM L-Glutamax

(Thermo Fisher Scientific, Grand Island, NY). Human Embryonic kidney line 293T was

purchased from ATCC (Gibco/Thermo Fisher Scientific, Grand Island, NY). Single-cell

clones of luciferase-expressing cell lines were generated by stably transducing wild-type

tumor lines with lentiviral vector encoding firefly luciferase (Lentigen Technology, Inc.,

Gaithersburg, MD), followed by cloning and selection of luciferase-positive clones. Whole

blood or buffy coats were collected from healthy volunteers at Oklahoma Blood Institute

(OBI, Oklahoma City, OK) with donors' written consent. CD4-positive and CD8-positive

human T cells were purified from buffy coats via positive selection using a 1:1 mixture of

CD4- and CD8- MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) according to

manufacturer's protocol.

(b) Creation of Chimeric Antigen Receptor (CAR) - Expression Vectors

CAR antigen-binding domains, ScFv, sequences were derived from human anti-CD22

ScFv or heavy chain variable fragments. CAR T constructs were generated by linking the

binder sequence in frame to CD8a linking and transmembrane domains (aa 123-191, Ref

sequence ID NP_001759.3), and then to 4-1BB (CD137, aa 214-255, UniProt sequence ID

Q07011) signaling domain and CD3 zeta signaling domain (CD247, aa 52-163, Ref sequence

ID: NP_000725.1). ID: NP_000725.1). CARCAR constructs sequences constructs were cloned sequences into a third were cloned into generation lentiviral lentiviral a third generation

plasmid backbone (Lentigen Technology Inc., Gaithersburg, MD). Lentiviral vector (LV)

containing supernatants were generated by transient transfection of HEK 293T cells and LV

pelleted by centrifugation of LV-containing supernatants, and stored at -80°C.

PCT/US2018/056011

(c) Primary T cell purification and transduction

Human primary T cells from healthy volunteers were purified from whole blood or

buffy coats using immunomagnetic bead selection of CD4+ and CD8+ cells according to

manufacturer's protocol (Miltenyi Biotec, Bergisch-Gladbach, Germany). T cells were

cultivated in TexMACS medium supplemented with 200 IU/ml IL-2 at a density of 0.3 to 2 X

106 cells/ml, activated 10 cells/ml, activated with with CD3/CD28 CD3/CD28 MACS® MACS GMP T Cell TransAct reagent (Miltenyi

Biotec) and transduced on day 2 with lentiviral vectors encoding CAR constructs in the

presence of 10 ug/ml protamine sulfate (Sigma-Aldrich, St. Louis, MO) overnight, and media

exchanged on day 3. Cultures were propagated in TexMACS medium supplemented with 200

IU/ml IL-2 until harvest on day 8-13.

(d) Immune effector assays (CTL and cytokine)

To determine cell-mediated cytotoxicity (CTL assay), 5,000 target cells stably

transduced with firefly luciferase were combined with CAR T cells at various effector to

target ratios and incubated overnight. SteadyGlo reagent (Promega, Madison WI) was added

to each well and the resulting luminescence quantified as counts per second (sample CPS).

Target only wells (max CPS) and target only wells plus 1% Tween-20 (min CPS) were used

to determine assay range. Percent specific lysis was calculated as: (1-(sample CPS-min

CPS)/(max CPS-min CPS)). Supernatants from co-cultures at E:T ratio of 10:1 were removed

and analyzed by ELISA (eBioscience, San Diego, CA) for IFNy, TNFa IFN, TNF and and IL-2 IL-2 concentration.

(e) Flow Cytometric analysis

For cell staining, half a million CAR T transduced cells were harvested from culture,

washed two times in cold AutoMACS buffer supplemented with 0.5% bovine serum albumin

(Miltenyi Biotec), and CAR surface expression detected by staining with CD22-Fc peptide

followed by anti Fc-PE conjugate (Jackson ImmunoResearch, West Grove, PA). Anti-CD4

antibody conjugated to VioBlue fluorophore (Miltenyi Biotec) was used where indicated, as

per vendors' protocol. Non-transduced cells were used as negative controls. Dead cells in all

studies were excluded by 7AAD staining (BD Biosciences, San Jose, CA). Cells were washed

twice and resuspended in 200 ul Staining Buffer before quantitative analysis by flow

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cytometry. Flow cytometric analysis was performed on a MACSQuant©10 MACSQuant®10 Analyzer (Miltenyi Biotec), and data plots were generated using FlowJo software (Ashland, OR).

(f) In vivo analysis of CAR function

All animal studies were approved by MI Bioresearch Animal Care and Use ommittee

(Ann Arbor, MI). A half million mouse-adapted Raji-luc cells were injected into the tail vein

(NOD.Cg-Prkdescia Il2rgtm1Wil/SzJ of NSG (NOD.Cg-Prkdescid Il2rg¹Wjl/SzJ ) ) mice. OnOn mice. day 6 6 day following Raji-luc following injection, Raji-luc injection,

tumor engraftment was measured by i.p. injection of 150 mg/kg luciferin and imaging on a

Xenogen IVIS-200 instrument (Caliper Biosciences, now Perkin Elmer, Shelton,

Connecticut). Images were analyzed using Living Image, version 4.1, software (Perkin

Elmer) and the bioluminescent signal flux for each mouse was expressed as average radiance

(photons per second per cm² per steradian). CAR T cells were administered to mice via tail

vein injection on Day 7. Imaging was performed on indicated days following CAR T

injection to establish the kinetics of tumor growth and eradication by CAR T cells.

RESULTS:

In order to evaluate the novel anti-CD22 fully human ScFv binding sequences, CAR

constructs in Set 1 were designed incorporating constructs 2246-2249: ScFv sequences

derived from phage display library, Table 1, ScFv1 (16P), ScFv2 (24P), ScFv3 (25P), ScFv4

(11S), ScFv5 (12S), and CAR construct 2202 (m971-positive control), as a tumor antigen

binding domain. In each CAR design, the tumor targeting domain was followed by a linker

and transmembrane domains derived from the human CD8 protein, a 4-1BB costimulatory

domain and a CD3 zeta signaling domain (Table 2 infra).

Table 2: List of CD22 - Targeting CAR Constructs incorporating ScFv sequences

CAR construct LTG# Composition

2202 ScFv1-CD8 TM-41BB-CD3 zeta 2246 ScFv2-CD8 TM-41BB-CD3 zeta Set 1 2247 ScFv3-CD8 TM-41BB-CD3 zeta

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2248 ScFv4-CD8 TM-41BB-CD3 zeta 2249 ScFv5-CD8 TM-41BB-CD3 zeta 2203 ScFv6-CD8 TM-41BB-CD3 zeta Set 2 2204 ScFv7-CD8 TM-41BB-CD3 zeta

Ligand-

CAR CAR independe Composition Composition LTG# nt CTL CAR CAR CAR CAR Binder Cytokine (K562, only only only ScFv K562-19) IL-2 IFNg CTL Response TNFa

2205 ScFv8-CD8 TM-41BB-CD3 zeta 2206 ScFv9-CD8 TM-41BB-CD3 zeta 2207 ScFv10-CD8 TM-41BB-CD3 zeta 2208 ScFv11-CD8 TM-41BB-CD3 zeta 2209 ScFv12-CD8 TM-41BB-CD3 zeta 2210 ScFv13-CD8 TM-41BB-CD3 zeta 2216 ScFv14-CD8 TM-41BB-CD3 zeta 2217 ScFv15-CD8 TM-41BB-CD3 zeta 2218 ScFv16-CD8 TM-41BB-CD3 zeta 2219 ScFv17-CD8 TM-41BB-CD3 zeta 2220 ScFv18-CD8 TM-41BB-CD3 zeta 1538 FMC63-CD8 TM-41BB-CD3 zeta Controls 2200 m971-CD8 TM-41BB-CD3 zeta

T cells Transduced with Anti-CD22 Chimeric Antigen Receptors Demonstrate Surface Expression and Cytolytic Activity.

a) Surface expression of anti-CD22 CARs

To evaluate the novel anti-CD22 CARs, lentiviral vectors (LV) encoding CAR

constructs under the control of human EFla promoter were generated as described in

Materials and Methods. Human primary T cells derived from healthy donors were transduced

lentiviral vectors encoding CARs. Non-transduced cells from same donor (termed UTD or

Mock) or GFP-transduced cells from same donor served as negative controls. Data is

representative of results from at least 3 assays from different donors.

TABLE 3. Summary of in vitro function of CARs targeting CD22

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ScFv1-CD8 TM-41BB-CD3 2202 zeta 16P med med low low low low ScFv2-CD8 TM-41BB-CD3 2246 zeta 24P low NA NA NA NA NA Set ScFv3-CD8 TM-41BB-CD3 Set 11 2247 zeta 25P non NA NA NA NA NA ScFv4-CD8 TM-41BB-CD3 2248 zeta 11s non NA NA NA NA NA ScFv5-CD8 TM-41BB-CD3 2249 zeta 12s non NA NA NA NA NA ScFv6-CD8 TM-41BB-CD3 2203 zeta 16P3 high high high low med high

ScFv7-CD8 TM-41BB-CD3 2204 zeta 16P16 high high high low med high

ScFv8-CD8 TM-41BB-CD3 2205 zeta 16P20 high high high low med high

ScFv9-CD8 TM-41BB-CD3 2206 zeta 16P2 high high high low med high

ScFv10-CD8 TM-41BB- 2207 CD3 zeta 16P6 high high high low med high

ScFv11-CD8 TM-41BB- 2208 CD3 zeta 16P10 high high high low med high

ScFv12-CD8 TM-41BB- Set 2 2209 CD3 zeta 16P17 high high high low low low ScFv13-CD8 TM-41BB- 2210 CD3 zeta 16P20v1 high high high low med high

ScFv14-CD8 TM-41BB- 2216 CD3 zeta 16P1 high high high low med high

ScFv15-CD8 TM-41BB- 2217 CD3 zeta 16P3v2 high high high low med high

ScFv16-CD8 TM-41BB- 2218 CD3 zeta 16P8 high high high low low low ScFv17-CD8 TM-41BB- 2219 CD3 zeta 16P13 high high high low med med ScFv18-CD8 TM-41BB- 2220 CD3 zeta 16P15 high high high low med high

m971-CD8 TM-41BB- 2200 CD3 zeta m971 high high low low low low Controls FMC63-CD8 TM-41BB- 1538 CD3 zeta FMC63 high high low low low low

Med: medium, CTL: cytotoxic T lymphocytes response (target cell lysis), NA: data not available, non: no lysis

T cells were activated on culture Day 0 with TransAct T cell reagent (Miltenyi Biotec, Inc.) in

the presence of IL-2 as described in Materials and Methods. On culture day 8-10, expression

of anti-CD22 CARs on the surface of transduced T cells was detected by protein L conjugated

to biotin, followed by staining with streptavidin-PE reagent. Alternatively, CD22-Fc peptide

(R&D Systems, Inc.) followed by staining with anti-Fc-PE antibody was used for CART

staining, and data acquired by flow cytometry (Figure 3). Except for CAR 2247,

which is comprised of lambda light chain (and thereby non-reactive with protein L), all CAR

constructs demonstrated surface CAR expression above 50-70% as detected by protein L

staining. By contrast, only CAR16P demonstrated CAR expression (~30%) when using the

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CD22-Fc peptide CD22-Fc peptide staining, staining, which which specifically specifically associates associates with thewith the anti-CD22 anti-CD22 ScFv - antigen ScFv - antigen

binding site (CAR 24P is not shown). These data indicate that whereas most CARs constructs

were expressed on T cell surface, only the CAR16P construct had assumed a ScFv configuration that maintianed CD22 protein binding.

b) Cytolytic assay and cytokine assay of anti-CD22 CARs

To demonstrate the cytolytic function of the generated CAR T cells, a luciferase-based

killing assay was performed by combining CAR-T with CD22-positive Raji-luc cells, CD22-

positive Reh-luc cells, CD22-negative K562-luc cells at E:T ratios of 20:1, 10:1, 5:1, or 2.5:1

in overnight cell killing assays as described in Materials and Methods (Figure 4). Anti CD19

CAR construct 1538, previously shown to react with Raji and Reh (CD19+) but not

K562(CD19) lines, was utilized as a positive control. Only CAR2202 (binder 16P) showed

dose-dependent, CD22-specific tumor killing, whereas CARs 2247 (25P), 2248 (11S), and

2249 (12S) had no tumor specific activity.

After determining that the novel human construct CAR2202 (16P) is functional in

vitro, its anti-tumor activity was tested in vivo, in an established NSG mouse xenograft model

of Raji Burkitts' lymphoma, as described in Material and Methods. Tumors were implanted

via tail vein on day 0, staging was performed on day 6, and mice were treated with 4 X

106CART 10°CART cells i.v. on day 7. Treatment groups were CAR16P (2202), CAR19 (1538) positive

control, CAR22 (2200 m971) positive control, and UTD (non-transduced T cells ) negative

control. As shown in Figure 5, positive control CART preparations CAR22 (2200 m971), and

CAR19 (1538) effectively inhibited tumor growth from study day 18 and onwards, whereas

the test construct CAR 2202 (16P) only mildly slowed down tumor progression, and its effect

was no longer discernable from the negative control treatment (UTD) after study day 32.

Therefore, ScFv binder 2202 (16P) had only weak anti-tumor activity in vitro and in vivo, and

there was a need for generating additional CAR constructs incorporating improved ScFv

binder sequences.

A set 2 of CAR constructs (LTG numbers 2203-2220) incorporating ScFv binder

sequences with improved affinity for CD22 (Table 1 infra, Set 2) were constructed as

described in the Materials and Methods. Derivation of the improved affinity ScFv binders is

described in Example 1. LV encoding Set 2 CAR constructs under the control of human EFla

promoter were generated and tested in vitro for expression and function as described above.

Briefly, T cells were activated on culture Day 0 with TransAct T cell reagent (active

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engagement of CD3 and CD28 antigens, Miltenyi Biotec, Inc.) in the presence of IL-2 as

described in Materials and Methods. On culture Day 8-10 CAR T cells were harvested and

assessed for CAR surface expression by flow cytometry. CTL activity was assessed by co-

incubation assay, and secretion of inflammatory cytokines was assessed by ELISA. A

comparative summary of functional outcomes for all CAR22 constructs is provided in Table

3. Positive control CAR constructs, as well as novel CAR22 candidates with most favorable

functional profile are noted in bold.

The set of 2 CAR constructs (LTG numbers 2203-2220) were tested by transducing

LV-encoded CAR sequences into cells from independent donors in at least three separate

experiments. Transduction of CART constructs from Set 2 into donor cells typically yielded

CAR expression ranging from 20% to 80%, as detected by CD22-Fc staining method and

consisted mostly of CD4+ T cells (Figure 6, select constructs).

CAR CTL activity was determined in an overnight assay by co-incubating CART cells

with luciferase-expressing tumor cells at E:T ratios ranging from 10:1 to 2.5:1 (Figure 7).

Residual luciferase activity originating in the surviving portion of tumor cell population at the

end of culture period was determined and % lysis was calculated as described in Materials

and Methods. The novel CD22-targeting CAR cells demonstrated strong killing activity in

CD22+ Raji lymphoma and in Reh leukemia lines, whereas negative control groups GFP and

UTD caused no lysis (Figure 7A). The exception to this rule was construct 2202 (16P), which

yielded relatively modest killing of tumor lines. CAR19-targeting control 1538 and CD22-

targeting control 2200 (m971) killed Raji and Reh tumors, as expected. K562 line, which is

CD22- and CD19-, showed background killing activity for the positive control constructs

2202 and 1538, which was 40% and 60% lysed tumor cells at E:T ratio of 10:1, respectively.

This activity may be due to indirect effect of inflammatory cytokines secreted by CART cells,

or contaminating NK/NKT activity. The killing activity of the test CAR22 constructs VS K56

was comparable in magnitude to control 2200 (m971), or slightly higher. To further delineate

the specificity of the novel CAR22 constructs, we employed K562 cells engineered to stably

express CD22, or CD19 (Figure 7B).

In K562-CD19 line, the positive control CAR19 (1538) yielded ~70% lysis for E:T

10:1, whereas the background killing activity of control CAR22 2200 (m971) was at only

~20% for E:T ratio of 10:1. By contrast, the % lysis produced by the majority of test CAR22

constructs under same E:T ratio was between 20% and 60%.

By comparison, in K562-CD22 line, the specific CTL activity of the CD22 CAR

control CAR22 2200 (m971) and the majority of novel CAR22 constructs was at 80%,

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whereas the non-specific killing activity of CAR19 control 1538 was only 20%. Therefore,

despite the sensitivity of K562 line to CAR constructs, the novel CD22 CARs tested all

demonstrated specific lytic activity against CD22-expressing targets.

Then, the concentration of inflammatory cytokines IFN-gamma, TNF-alpha and IL-2

secreted by CAR T cells transduced with CAR22 constructs, when challenged by CD22-

positive cell lines Raji and REH (Figure 8) were then measured. CAR T cells alone controls

were included for each construct, in order to test for basal levels of cytokine production.

Levels of TNF-alpha, IFN-gamma and IL-2 were strongly induced by T cells exposed to

CD22+ Raji cells, CD22 Raji cells, however, however, for for most most CAR22 CAR22 constructs, constructs, Reh Reh tumors tumors mediated mediated induction induction of of

IFNg and TNFa only, but not IL-2. For a subset of constructs, T cells only control groups also

showed induction of cytokines, raising the possibility that these constructs are activated in the

absence of specific ligands. Therefore, CAR design and binder choice are not trivial, as some

binders active in a soluble IgG or ScFv format and amenable to expression on T cell surface in

a CAR T format, are nevertheless inefficient in killing or producing cytokines when co-

incubated with CD22-positive tumors. In case of LTG2217 (16P3v2 binder) and LTG 2220

(16P15), for example, IL-2 and TNF-alpha were tonically produced by the construct

indicating self-activation of the T cell in the absence of tumor target. This would likely prove

toxic for clinical use and LTG2217 and LTG2220 are therefore disqualified as a therapeutic

candidates.

To To avoid avoid the the possibility possibility of of non-specific non-specific activation activation of of CAR22 CAR22 cells, cells, we we have have identified identified

constructs with no/minimal secretion of inflammatory cytokines in the absence of specific

tumors: LTG2209 (16P17), LTG2218 (16P8) and LTG2219 (16P13).

Next, novel CAR22 constructs 2219 and 2209 were tested in the NSG Raji xenograft

tumor model. Constructs 2200 (m971) and 1538 (FMC63) served as positive controls, and

tumor alone (TA) and non-transduced T cells (UTD) served as negative controls.

Experimental procedures were performed as detailed in Materials and Methods. Raji-

luciferase expressing tumor cells were implanted in mice on day 0, followed by CART

treatment of day 7. Tumor progression and CART activity were determined by weekly

bioluminescence measurements starting on study day 6 (Figure 9). In comparison to negative

control groups, TA and UTD, in which tumor growth proceeded unabated from day 6 and on,

CAR test constructs 2209 and 2209 inhibited tumor progression, and by day 21 have reduced

tumor bioluminescence to baseline at treatment initiation (day 6). The anti-tumor effect of the

test constructs 2209 and 2209 was equal to, or greater than that produced by the positive

control CD22 CAR construct 2200 (m971).

In summary, high functionality of novel fully human, improved-affinity anti-CD22

CAR constructs derived from the yeast screening library, LTG numbers 2203 through 2220

(Table 2 infra), was demonstrated. Notably CAR constructs, 2209, 2219, 2218, were superior

or showed a different activity profile to the positive control, LTG2220 (m971), and thus are

expected to have potent therapeutic activity.

Each of the applications and patents cited in this text, as well as each document or

reference cited in each of the applications and patents (including during the prosecution of

each issued patent; "application cited documents"), and each of the PCT and foreign

applications or patents corresponding to and/or claiming priority from any of these

applications and patents, and each of the documents cited or referenced in each of the

application cited documents, are hereby expressly incorporated herein by reference, and may

be employed in the practice of the invention. More generally, documents or references are

cited in this text, either in a Reference List before the claims, or in the text itself; and, each of

these documents or references ("herein cited references"), as well as each document or

reference cited in each of the herein cited references (including any manufacturer's

specifications, instructions, etc.), is hereby expressly incorporated herein by reference.

The foregoing description of some specific embodiments provides sufficient

information that others can, by applying current knowledge, readily modify or adapt for

various applications such specific embodiments without departing from the generic concept,

and, therefore, such adaptations and modifications should and are intended to be

comprehended within the meaning and range of equivalents of the disclosed embodiments. It

is to be understood that the phraseology or terminology employed herein is for the purpose of

description and not of limitation. In the drawings and the description, there have been

disclosed exemplary embodiments and, although specific terms may have been employed,

they are unless otherwise stated used in a generic and descriptive sense only and not for

purposes of limitation, the scope of the claims therefore not being SO so limited. Moreover, one

skilled in the art will appreciate that certain steps of the methods discussed herein may be

sequenced in alternative order or steps may be combined. Therefore, it is intended that the

appended claims not be limited to the particular embodiment disclosed herein. Those skilled

in the art will recognize, or be able to ascertain using no more than routine experimentation,

many equivalents to the embodiments of the invention described herein. Such equivalents are

encompassed by the following claims.

SEQUENCES OF THE DISCLOSURE

The nucleic and amino acid sequences listed below are shown using standard letter

abbreviations for nucleotide bases, and three letter code for amino acids, as defined in 37 C.F.R.

1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is

understood as included by any reference to the displayed strand. In the accompanying sequence

listing:

SEQ ID NO: 1 is the nucleic acid sequence of the CD22-specific binder (scFvl) (scFv1) 16P:

CAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGGTGAAGCCGTCACAGAC CAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGGTGAAGCCGTCACAGAC GCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGTGAGTTCTAATAGCO GCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGTGAGTTCTAATAGCGO GGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAGGATTGGAATGGCTCC GGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAGGATTGGAATGGCTCG GCAGGACTTATTATAGAAGTAAGTGGTACAACGATTATGCAGTCTCTGTG GCAGGACTTATTATAGAAGTAAGTGGTACAACGATTATGCAGTCTCTGTC AAATCTCGCATCACCATTAACCCAGACACGTCTAAGAATCAGTTCAGTCTT CAACTCAACTCTGTAACCCCCGAAGATACAGCGGTCTACTACTGTGCTCA CAACTCAACTCTGTAACCCCCGAAGATACAGCGGTCTACTACTGTGCTCA GGAGGTGCAACCCCACGATGCTTTTGATATCTGGGGCCAGGGTACCATGO GGAGGTGCAACCCCACGATGCTTTTGATATCTGGGGCCAGGGTACCATGG TTACGGTGTCTTCTGGGGGAGGGGGGTCCGGTGGGGGAGGATCAGGGGGT ITACGGTGTCTTCTGGGGGAGGGGGGTCCGGTGGGGGAGGATCAGGGGGT GGGGGCAGCGACATACAAATGACGCAATCCCCGTCTTCTGTTTCTGCGTCT GTCGGAGATAAAGTAACAATAACCTGTCGAGCGTCACAGGACGTTAGTGG GTCGGAGATAAAGTAACAATAACCTGTCGAGCGTCACAGGACGTTAGTGG CTGGCTTGCGTGGTATCAGCAAAAACCGGGGCTCGCCCCGCAATTGCTTA TATTTGGAGCGAGTACTCTTCAGGGCGAGGTACCTAGCAGATTTTCTGGGT CCGGCTCAGGTACGGACTTCACCCTGACCATATCTAGCTTGCAGCCTGAA CCGGCTCAGGTACGGACTTCACCCTGACCATATCTAGCTTGCAGCCTGAA GATTTCGCCACCTACTATTGTCAACAGGCGAAGAACTTTCCATATACGTTO GATTTCGCCACCTACTATTGTCAACAGGCGAAGAACTTTCCATATACGTTC GGGCAGGGTACGAAATTGGAGATAAAA SEQ ID NO: 2 is the amino acid sequence of the CD22-specific binder (scFv1) 16P:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWL TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQ PHDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK PHDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIKR TLTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIKR

SEQ ID NO: 3 is the nucleic acid sequence of the CD22 CAR LTG2202 (LP-scFv1- CD8TM-41BB-CD3zeta):

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGO ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA FTCCTCCTGATCCCACAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGGT TCCTCCTGATCCCACAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGGT GAAGCCGTCACAGACGCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGT GAAGCCGTCACAGACGCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGT GAGTTCTAATAGCGCGGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAG GAGTTCTAATAGCGCGGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAG

GATTGGAATGGCTCGGCAGGACTTATTATAGAAGTAAGTGGTACAACGA GATTGGAATGGCTCGGCAGGACTTATTATAGAAGTAAGTGGTACAACGAT ATGCAGTCTCTGTGAAATCTCGCATCACCATTAACCCAGACACGTCTAA TATGCAGTCTCTGTGAAATCTCGCATCACCATTAACCCAGACACGTCTAAG AATCAGTTCAGTCTTCAACTCAACTCTGTAACCCCCGAAGATACAGCGGT CTACTACTGTGCTCAGGAGGTGCAACCCCACGATGCTTTTGATATCTGGGG CTACTACTGTGCTCAGGAGGTGCAACCCCACGATGCTTTTGATATCTGGGG CCAGGGTACCATGGTTACGGTGTCTTCTGGGGGAGGGGGGTCCGGTGGGG CCAGGGTACCATGGTTACGGTGTCTTCTGGGGGAGGGGGGTCCGGTGGGGE GAGGATCAGGGGGTGGGGGCAGCGACATACAAATGACGCAATCCCCGTC TTCTGTTTCTGCGTCTGTCGGAGATAAAGTAACAATAACCTGTCGAGCGTC TTCTGTTTCTGCGTCTGTCGGAGATAAAGTAACAATAACCTGTCGAGCGTC ACAGGACGTTAGTGGCTGGCTTGCGTGGTATCAGCAAAAACCGGGGCTCG CCCCGCAATTGCTTATATTTGGAGCGAGTACTCTTCAGGGCGAGGTACCTA CCCCGCAATTGCTTATATTTGGAGCGAGTACTCTTCAGGGCGAGGTACCT= GCAGATTTTCTGGGTCCGGCTCAGGTACGGACTTCACCCTGACCATATCTA GCAGATTTTCTGGGTCCGGCTCAGGTACGGACTTCACCCTGACCATATCTA GCTTGCAGCCTGAAGATTTCGCCACCTACTATTGTCAACAGGCGAAGAA GCTTGCAGCCTGAAGATTTCGCCACCTACTATTGTCAACAGGCGAAGAAC TTTCCATATACGTTCGGGCAGGGTACGAAATTGGAGATAAAAGCGGCCGC ITTCCATATACGTTCGGGCAGGGTACGAAATTGGAGATAAAAGCGGCCGC AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT ACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCA CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGE GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACC GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG SEQ ID NO: 4 is the amino acid sequence of the CD222 CARLTG2202 CD22 CAR LTG2202(LP-scFvl- (LP-scFv1- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS) MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSI QLNSVTPEDTAVYYCAQEVQPHDAFDIWGQGTMVTVSSGGGGSGGGGSG QLNSVTPEDTAVYYCAQEVQPHDAFDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLI GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 5 is the amino acid sequence of the scFv1 (16P) LCDR1:

QDVSGW SEQ ID NO: 6 is the amino acid sequence of the scFvl scFv1 (16P) LCDR2:

GAS scFvl (16P) LCDR3: SEQ ID NO: 7 is the amino acid sequence of the scFv1

QQAKNFPYT SEQ ID NO: 8 is the amino acid sequence of the scFv1 scFvl (16P) HCDR1:

GDSVSSNSAA SEQ ID NO: 9 is the amino acid sequence of the scFv1 (16P) HCDR2:

TYYRSKWYN SEQ ID NO: 10 is the amino acid sequence of the scFv1 (16P) HCDR3:

AQEVQPHDAFDI SEQ ID NO: 11 is the nucleic acid sequence of the CD22-specific binder (scFv2)

24P:

CAAGTACAGCTGCAACAATCTGGCCCTGGGCTTGTGAAACCCTCTCAGAG CAAGTACAGCTGCAACAATCTGGCCCTGGGCTTGTGAAACCCTCTCAGAC FTTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGTTAGTTCTAACAGCGC TTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGTTAGTTCTAACAGCGC CGCTTGGAACTGGATTAGACAGAGCCCCAGTCGGGGACTCGAATGGCTTG CGCTTGGAACTGGATTAGACAGAGCCCCAGTCGGGGACTCGAATGGCTTG GCCGGACTTATTATCGCAGTAAATGGTATAATGATTATGCTGTGAGTGTGA AAAGTAGGATCACAATCAACCCCGATACGAGCAAGAATCAATTCTCATTG AAAGTAGGATCACAATCAACCCCGATACGAGCAAGAATCAATTCTCATTO CAACTGAACAGCGTCACTCCCGAGGATACAGCTGTATATTATTGTGCAA CAACTGAACAGCGTCACTCCCGAGGATACAGCTGTATATTATTGTGCAAG AGAAGGTGGGTGGTATGGCGAGATGGATGTATGGGGGAAAGGAACTACG AGAAGGTGGGTGGTATGGCGAGATGGATGTATGGGGGAAAGGAACTACG GTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTGGAGGCTCTGGAGG GTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTGGAGGCTCTGGAGG AGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGCTACTCTGAGCGTTA AGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGCTACTCTGAGCGTTA GTCCGGGTGAAAGGGCCTCACTCTCTTGTCGAGCTTCACAGTCAGTCTCT TCCGGGTGAAAGGGCCTCACTCTCTTGTCGAGCTTCACAGTCAGTCTCTT CCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGGCGCCCCGCTTGCTC CCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGGCGCCCCGCTTGCTC ATTTACGACGCAAGCACACGAGCGACAGGCATTCCAGACAGATTTTCTGE ATTTACGACGCAAGCACACGAGCGACAGGCATTCCAGACAGATTTTCTGG TTCTGGTTCTGGCACGGACTTTACTCTTACTATAAACTCACTTGAGGCAGA TTCTGGTTCTGGCACGGACTTTACTCTTACTATAAACTCACTTGAGGCAGA GGATGCTGCGACTTACTATTGTCACCAATCAAGCTCTCTGCCTTACACCT GGATGCTGCGACTTACTATTGTCACCAATCAAGCTCTCTGCCTTACACCTT TGGGCAAGGCACCAAACTCGAAATCAAG SEQ ID NO: 12 is the amino acid sequence of the CD22-specific binder (scFv2) 24P:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGI TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREGG WYGEMDVWGKGTTVTVSSGGGGSGGGGSGGGGSEIVLTQSPATLSVSPGER ASLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASTRATGIPDRFSGSGSGTDF ASLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASTRATGIPDRFSGSGSGTDF TLTINSLEAEDAATYYCHQSSSLPYTFGQGTKLEIKR SEQ ID NO: 13 is the nucleic acid sequence of the CD22 CAR LTG2246 (LP-scFv2- CD8TM-41BB-CD3zeta):

ATGCTGCTGTTGGTGACATCACTTCTGCTCTGTGAACTCCCCCATCCAGCC ATGCTGCTGTTGGTGACATCACTTCTGCTCTGTGAACTCCCCCATCCAGCO TTTCTGCTTATACCGCAAGTACAGCTGCAACAATCTGGCCCTGGGCTTGTG TTTCTGCTTATACCGCAAGTACAGCTGCAACAATCTGGCCCTGGGCTTGTG AAACCCTCTCAGACTTTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGTT AAACCCTCTCAGACTTTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGT AGTTCTAACAGCGCCGCTTGGAACTGGATTAGACAGAGCCCCAGTCGGGC AGTTCTAACAGCGCCGCTTGGAACTGGATTAGACAGAGCCCCAGTCGGGG

ACTCGAATGGCTTGGCCGGACTTATTATCGCAGTAAATGGTATAATGATTA ACTCGAATGGCTTGGCCGGACTTATTATCGCAGTAAATGGTATAATGATTA TGCTGTGAGTGTGAAAAGTAGGATCACAATCAACCCCGATACGAGCAAG TGCTGTGAGTGTGAAAAGTAGGATCACAATCAACCCCGATACGAGCAAGA ATCAATTCTCATTGCAACTGAACAGCGTCACTCCCGAGGATACAGCTGTA TATTATTGTGCAAGAGAAGGTGGGTGGTATGGCGAGATGGATGTATGGGG FATTATTGTGCAAGAGAAGGTGGGTGGTATGGCGAGATGGATGTATGGGG GAAAGGAACTACGGTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTG GAAAGGAACTACGGTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTG GAGGCTCTGGAGGAGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGCT GAGGCTCTGGAGGAGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGCT ACTCTGAGCGTTAGTCCGGGTGAAAGGGCCTCACTCTCTTGTCGAGCTTCA CAGTCAGTCTCTTCCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGGC CAGTCAGTCTCTTCCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGG GCCCCGCTTGCTCATTTACGACGCAAGCACACGAGCGACAGGCATTCCAG ACAGATTTTCTGGTTCTGGTTCTGGCACGGACTTTACTCTTACTATAAAC ACAGATTTTCTGGTTCTGGTTCTGGCACGGACTTTACTCTTACTATAAACT CACTTGAGGCAGAGGATGCTGCGACTTACTATTGTCACCAATCAAGCTCT CACTTGAGGCAGAGGATGCTGCGACTTACTATTGTCACCAATCAAGCTCT CTGCCTTACACCTTTGGGCAAGGCACCAAACTCGAAATCAAGGTTACGGT CTGCCTTACACCTTTGGGCAAGGCACCAAACTCGAAATCAAGGTTACGGT ATCATCTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGG ATCATCTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGG CCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCC CGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGAT CGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGAT ATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCG ATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCG ATGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACAT CTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACAT CTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCG CGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGA ATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGT ATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGT GCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGO GCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGG CGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGA CGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGA TGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGC AAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGAT AAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGAT ACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG ACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 14 is the amino acid sequence of the CD22 CAR LTG2246 (LP-scFv2- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSM SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFS SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAREGGWYGEMDVWGKGTTVTVSSGGGGSGGGGSG QLNSVTPEDTAVYYCAREGGWYGEMDVWGKGTTVTVSSGGGGSGGGGSG GGGSEIVLTQSPATLSVSPGERASLSCRASQSVSSYLAWYQQKPGQAPRLLIY DASTRATGIPDRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPYTFGQGTK DASTRATGIPDRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPYTFGQGTK LEIKVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDI ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLD KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 15 is the amino acid sequence of the scFv2 (24P) LCDR1:

QSVSSY

SEQ ID NO: 16 is the amino acid sequence of the scFv2 (24P) LCDR2:

DAS

SEQ ID NO: 17 is the amino acid sequence of the scFv2 (24P) LCDR3:

HQSSSLPYT

SEQ ID NO: 18 is the amino acid sequence of the scFv2 (24P) HCDR1:

GDSVSSNSAA SEQ ID NO: 19 is the amino acid sequence of the scFv2 (24P) HCDR2:

TYYRSKWYN SEQ ID NO: 20 is the amino acid sequence of the scFv2 (24P) HCDR3:

AREGGWYGEMDV SEQ ID NO: 21 is the nucleic acid sequence of the CD22-specific binder (scFv3)

25P:

CAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGTTAAGCCGTCCCAAAC CAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGTTAAGCCGTCCCAAA ACTGTCTTTGACGTGCGCTATTAGTGGCGACAGCGTATCATCCAATTCTGC ACTGTCTTTGACGTGCGCTATTAGTGGCGACAGCGTATCATCCAATTCTG TGCTTGGAACTGGATTAGACAGTCACCGTCCAGAGGCTTGGAATGGCTGG GCAGGACGTACTACCGCTCAAAATGGTATAACGATTACGCGGTTAGTGTC GCAGGACGTACTACCGCTCAAAATGGTATAACGATTACGCGGTTAGTGTC AAATCCAGGATTACCATTAACCCTGACACAAGTAAGAATCAGTTTTCTCTT CAGCTGAATTCCCTGACTCCTGAGGATACGGCCGTTTACTACTGTGCCCGA GAACACCAGAATGAGGCGGCTTTTGATATTTGGGGGCAAGGAACAATGGT CACAGTTAGCAGTGGGGGGGGTGGCTCCGGGGGAGGTGGTTCCGGCGGC CACAGTTAGCAGTGGGGGGGGTGGCTCCGGGGGAGGTGGTTCCGGCGG GGTGGTTCTCAATCCGTCCTGACACAACCTCCCTCAGCGAGCGGGACTCC GGTGGTTCTCAATCCGTCCTGACACAACCTCCCTCAGCGAGCGGGACTCC CGGTCAAAGGGTGACCATCTCTTGTTCTGGGGGAGGTAGTAACATCGGGA CAAATACTGCGTCCTGGTATCAGCAACTCCCTGGGACCGCTCCCAAGTTGT CAAATACTGCGTCCTGGTATCAGCAACTCCCTGGGACCGCTCCCAAGTTGT TGATATATCGCAATACGCAACGACCTAGTGGGATACCTGATAGATTCAGC GGAAGCAAAAGTGGTACGAGTGCGTCTTTGGCAATATCTGGCCTCCAGTC CGAGGACGAAGCGGATTACTATTGTGCGGCCTGGGATGACTCACTGAATG CGAGGACGAAGCGGATTACTATTGTGCGGCCTGGGATGACTCACTGAATG GTTATGTGTTCGGTGCAGGTACTCAACTCACCGTACTTGGT GTTATGTGTTCGGTGCAGGTACTCAACTCACCGTACTTGGT SEQ ID NO: 22 is the amino acid sequence of the CD22-specific binder (scFv3) 25P:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSLTPEDTAVYYCAREHQ TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSLTPEDTAVYYCAREHQ NEAAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRV NEAAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRV TISCSGGGSNIGTNTASWYQQLPGTAPKLLIYRNTQRPSGIPDRFSGSKSGTSA TISCSGGGSNIGTNTASWYQQLPGTAPKLLIYRNTQRPSGIPDRFSGSKSGTSA SLAISGLQSEDEADYYCAAWDDSLNGYVFGAGTQLTVLG SLAISGLQSEDEADYYCAAWDDSLNGYVFGAGTQLTVLG SEQ ID NO: 23 is the nucleic acid sequence of the CD22 CAR LTG2247 (LP-scFv3- CD8TM-41BB-CD3zeta):

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGTT FTCCTCCTGATCCCACAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGTT AAGCCGTCCCAAACACTGTCTTTGACGTGCGCTATTAGTGGCGACAGCGT AATCATCCAATTCTGCTGCTTGGAACTGGATTAGACAGTCACCGTCCAGAG ATCATCCAATTCTGCTGCTTGGAACTGGATTAGACAGTCACCGTCCAGAG

GCTTGGAATGGCTGGGCAGGACGTACTACCGCTCAAAATGGTATAACGAT GCTTGGAATGGCTGGGCAGGACGTACTACCGCTCAAAATGGTATAACGAT TACGCGGTTAGTGTCAAATCCAGGATTACCATTAACCCTGACACAAGTAA TACGCGGTTAGTGTCAAATCCAGGATTACCATTAACCCTGACACAAGTAA GAATCAGTTTTCTCTTCAGCTGAATTCCCTGACTCCTGAGGATACGGCCGT GAATCAGTTTTCTCTTCAGCTGAATTCCCTGACTCCTGAGGATACGGCCGT TTACTACTGTGCCCGAGAACACCAGAATGAGGCGGCTTTTGATATTTGGG ITACTACTGTGCCCGAGAACACCAGAATGAGGCGGCTTTTGATATTTGG GGCAAGGAACAATGGTCACAGTTAGCAGTGGGGGGGGTGGCTCCGGGGG GGCAAGGAACAATGGTCACAGTTAGCAGTGGGGGGGGTGGCTCCGGGGG AGGTGGTTCCGGCGGCGGTGGTTCTCAATCCGTCCTGACACAACCTCCCTC AGCGAGCGGGACTCCCGGTCAAAGGGTGACCATCTCTTGTTCTGGGGGAG GTAGTAACATCGGGACAAATACTGCGTCCTGGTATCAGCAACTCCCTGGG ACCGCTCCCAAGTTGTTGATATATCGCAATACGCAACGACCTAGTGGGAT ACCGCTCCCAAGTTGTTGATATATCGCAATACGCAACGACCTAGTGGGAT ACCTGATAGATTCAGCGGAAGCAAAAGTGGTACGAGTGCGTCTTTGGCAA ACCTGATAGATTCAGCGGAAGCAAAAGTGGTACGAGTGCGTCTTTGGCAA TATCTGGCCTCCAGTCCGAGGACGAAGCGGATTACTATTGTGCGGCCTGG TATCTGGCCTCCAGTCCGAGGACGAAGCGGATTACTATTGTGCGGCCTGG GATGACTCACTGAATGGTTATGTGTTCGGTGCAGGTACTCAACTCACCGTA CTTGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGG CTTGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGC CCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCC CCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCC GGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATA GGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATA TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGG TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGC TGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATC TGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATC TTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGG ATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGC ATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGC GTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAA TCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTG TCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTG CTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGO CTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGC GGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGAT GGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGAT GGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGA AAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA AAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 24 is the amino acid sequence of the CD22 CAR LTG2247 (LP-scFv3- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQF QLNSLTPEDTAVYYCAREHQNEAAFDIWGQGTMVTVSSGGGGSGGGGSGGG QLNSLTPEDTAVYYCAREHQNEAAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSQSVLTQPPSASGTPGQRVTISCSGGGSNIGTNTASWYQQLPGTAPKLLI GSQSVLTQPPSASGTPGQRVTISCSGGGSNIGTNTASWYQQLPGTAPKLLIYR NTQRPSGIPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFGA NTQRPSGIPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFGA GTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGI GTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLD KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 25 is the amino acid sequence of the scFv3 (25P) LCDR1:

GSNIGTNT

SEQ ID NO: 26 is the amino acid sequence of the scFv3 (25P) LCDR2:

RNT RNT

97 wo 2019/079249 WO PCT/US2018/056011

SEQ ID NO: 27 is the amino acid sequence of the scFv3 (25P) LCDR3:

AAWDDSLNGYV SEQ ID NO: 28 is the amino acid sequence of the scFv3 (25P) HCDR1:

GDSVSSNSAA SEQ ID NO: 29 is the amino acid sequence of the scFv3 (25P) HCDR2:

TYYRSKWYN SEQ ID NO: 30 is the amino acid sequence of the scFv3 (25P) HCDR3:

AREHQNEAAFDI SEQ ID NO: 31 is the nucleic acid sequence of the CD22-specific binder (scFv4) 11s:

CAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGTTAAGCCATCCCAAA0 CAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGTTAAGCCATCCCAAAC TCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGTGTCCAGCAATTCTGO FCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGTGTCCAGCAATTCTGC AACCTGGAATTGGATCCGGCAGAGTCCGAGTGGCGGTTTGGAATGGCTC GACGCACTTACTACAGGAGCAAATGGTACGATGATTATGCTGTTTCTGTC GACGCACTTACTACAGGAGCAAATGGTACGATGATTATGCTGTTTCTGTG CGCTCTCGAATCACCATGAATCCTGATACTTCTAAGAACCAATTTTCTTTC CGCTCTCGAATCACCATGAATCCTGATACTTCTAAGAACCAATTTTCTTTG CAGTTGAACTCCGTCACGCCTGAAGATACTGCGGTCTACTATTGCGCACG CGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCAAGGAACATTGGTCA CGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCAAGGAACATTGGTCA CGGTCTCCTCTGGTGGAGGAGGATCAGGAGGCGGGGGTTCAGGTGGAGGT GGGAGCGATATTCAACTTACGCAGTCTCCGAGCAGTCTTTCTGCTTCCGTG GGGAGCGATATTCAACTTACGCAGTCTCCGAGCAGTCTTTCTGCTTCCGTG- GGAGACCGAGTGACGATTACTTGTAGGGCATCTCAGTCAATAAGTTCCTA TCTTAACTGGTATCAGCAGAAGCCTGGAAAGGCTCCAAAACTTCTTATTTA TGCCGCATCCTCATTGCAATCCGGCGTGCCTTCCCGATTTTCCGGATCTGG TGCCGCATCCTCATTGCAATCCGGCGTGCCTTCCCGATTTTCCGGATCTGG CTCAGGCACTGACTTTACCTTGACTATTAGTTCCCTTCAACCAGAAGATTT CTCAGGCACTGACTTTACCTTGACTATTAGTTCCCTTCAACCAGAAGATTT TGCTACCTATTACTGCCAACAATCATACAGTACCCCATATACATTCGGCCA IGCTACCTATTACTGCCAACAATCATACAGTACCCCATATACATTCGGCCA AGGCACGAAATTGGAGATTAAA AGGCACGAAATTGGAGATTAAA SEQ ID NO: 32 is the amino acid sequence of the CD22-specific binder (scFv4) 11s:

9VVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSATWNWIRQSPSGGLEWLG QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSATWNWIRQSPSGGLEWLGR TYYRSKWYDDYAVSVRSRITMNPDTSKNQFSLQLNSVTPEDTAVYYCAREG TYYRSKWYDDYAVSVRSRITMNPDTSKNQFSLQLNSVTPEDTAVYYCAREG VAGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDR VAGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDR VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIKR LTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIKR SEQ ID NO: 33 is the nucleic acid sequence of the CD22 CAR LTG2248 (LP-scFv4- CD8TM-41BB-CD3zeta):

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGT7 ITCCTCCTGATCCCACAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGTT AAGCCATCCCAAACTCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGT AAGCCATCCCAAACTCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGT GTCCAGCAATTCTGCAACCTGCAATTCGATCCGGCAGAGTCCGAGTGGCG GTCCAGCAATTCTGCAACCTGGAATTGGATCCGGCAGAGTCCGAGTGGCG

GTTTGGAATGGCTCGGACGCACTTACTACAGGAGCAAATGGTACGATGAT GTTTGGAATGGCTCGGACGCACTTACTACAGGAGCAAATGGTACGATGA ATGCTGTTTCTGTGCGCTCTCGAATCACCATGAATCCTGATACTTCTAAC ATGCTGTTTCTGTGCGCTCTCGAATCACCATGAATCCTGATACTTCTAAG AACCAATTTTCTTTGCAGTTGAACTCCGTCACGCCTGAAGATACTGCGGT TACTATTGCGCACGCGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCA TACTATTGCGCACGCGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCA AGGAACATTGGTCACGGTCTCCTCTGGTGGAGGAGGATCAGGAGGCGGG AGGAACATTGGTCACGGTCTCCTCTGGTGGAGGAGGATCAGGAGGCGGG GGTTCAGGTGGAGGTGGGAGCGATATTCAACTTACGCAGTCTCCGAGCAG TCTTTCTGCTTCCGTGGGAGACCGAGTGACGATTACTTGTAGGGCATCTCA TCTTTCTGCTTCCGTGGGAGACCGAGTGACGATTACTTGTAGGGCATCTCA GTCAATAAGTTCCTATCTTAACTGGTATCAGCAGAAGCCTGGAAAGGCTC GTCAATAAGTTCCTATCTTAACTGGTATCAGCAGAAGCCTGGAAAGGCT CAAAACTTCTTATTTATGCCGCATCCTCATTGCAATCCGGCGTGCCTTCC< CAAAACTTCTTATTTATGCCGCATCCTCATTGCAATCCGGCGTGCCTTCC GATTTTCCGGATCTGGCTCAGGCACTGACTTTACCTTGACTATTAGTTCCC GATTTTCCGGATCTGGCTCAGGCACTGACTTTACCTTGACTATTAGTTCCC TTCAACCAGAAGATTTTGCTACCTATTACTGCCAACAATCATACAGTACC TTCAACCAGAAGATTTTGCTACCTATTACTGCCAACAATCATACAGTACCC CATATACATTCGGCCAAGGCACGAAATTGGAGATTAAAGCGGCCGCAACT CATATACATTCGGCCAAGGCACGAAATTGGAGATTAAAGCGGCCGCAACT ACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCA ACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCA ACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCG ACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCG TGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGC TGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGC TGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACT GCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATG GCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATG CGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCC CGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCC TGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCC TGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCC GCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCT GCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCT GAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGA GAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGA CGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAG GACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGA GACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGA AATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCT AATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCT GTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATA GTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATA TGCAAGCACTCCCACCCCGG SEQ ID NO: 34 is the amino acid sequence of the CD22 CAR LTG2248 (LP-scFv4- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SATWNWIRQSPSGGLEWLGRTYYRSKWYDDYAVSVRSRITMNPDTSKNG SATWNWIRQSPSGGLEWLGRTYYRSKWYDDYAVSVRSRITMNPDTSKNQFS LQLNSVTPEDTAVYYCAREGVAGDFDYWGQGTLVTVSSGGGGSGGGGSG LQLNSVTPEDTAVYYCAREGVAGDFDYWGQGTLVTVSSGGGGSGGGGSGG GGSDIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY, GGSDIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLE SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEI KAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIV KAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW APLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRD EEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRD PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG LSTATKDTYDALHMQALPPR

SEQ ID NO: 35 is the amino acid sequence of the scFv4 (11s) LCDR1:

QSISSY

SEQ ID NO: 36 is the amino acid sequence of the scFv4 (11s) LCDR2:

AAS wo 2019/079249 WO PCT/US2018/056011

SEQ ID NO: 37 is the amino acid sequence of the scFv4 (11s) LCDR3:

QQSYSTPYT SEQ ID NO: 38 is the amino acid sequence of the scFv4 (11s) HCDR1:

GDSVSSNSAT SEQ ID NO: 39 is the amino acid sequence of the scFv4 (11s) HCDR2:

TYYRSKWYD SEQ ID NO: 40 is the amino acid sequence of the scFv4 (11s) HCDR3:

AREGVAGDFDY AREGVAGDFDY SEQ ID NO: 41 is the nucleic acid sequence of the CD22-specific binder (scFv5) 12s:

CAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTTGTTAAACCATCACAGA CAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTTGTTAAACCATCACAGAC GCTCTCACTGACCTGTGCCATCTCTGGAGACAGTGTAAGTTCTAACTCAGC CGCGTGGAATTGGATTAGACAATCACCAAGCCGGGGACTTGAATGGCTTG CGCGTGGAATTGGATTAGACAATCACCAAGCCGGGGACTTGAATGGCTTG GTCGGACGTACTATAGATCTAAGTGGTATAATGACTACGCAGTGTCAGTC GTCGGACGTACTATAGATCTAAGTGGTATAATGACTACGCAGTGTCAGTG AAATCACGGATAACCATAAACCCTGACACCAGCAAAAACCAATTTTCTCT TCAGCTTAATTCCGTCACGCCAGAAGATACGGCCGTTTACTACTGTGCGA ICAGCTTAATTCCGTCACGCCAGAAGATACGGCCGTTTACTACTGTGCGA GGGAAGGTGATGACGCATTGGACATCTGGGGTCAGGGGACCATGGTGACT GGGAAGGTGATGACGCATTGGACATCTGGGGTCAGGGGACCATGGTGACT GTCTCTTCCGGCGGGGGGGGTAGTGGAGGGGGTGGCTCAGGTGGTGGCGG GTCAGATATACAAATGACACAGAGCCCTAGTAGTCTGAGTGCTTCAGTGG GTCAGATATACAAATGACACAGAGCCCTAGTAGTCTGAGTGCTTCAGTGG GCGACCGCGTAACTATAACCTGTAGAGCATCCCAAAGCATTTCCCACTTC CTTAATTGGTACCAGCAGAAGCCGGGCACAGCGCCCAAACTCCTGATCAC CACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCCGGTTTAGTGGGTCAG CACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCCGGTTTAGTGGGTCAC TAGCGGTACAGATTTCACTCTCACGATAAACTCCCTTCAGCCTGAGGAC GTAGCGGTACAGATTTCACTCTCACGATAAACTCCCTTCAGCCTGAGGAC CTGGCGACATATTACTGTCAACAATCCTATACCACCCCACTGACATTCGGA CTGGCGACATATTACTGTCAACAATCCTATACCACCCCACTGACATTCGGA GGGGGCACAAAACTGGAGATCAAA GGGGGCACAAAACTGGAGATCAAA SEQ ID NO: 42 is the amino acid sequence of the CD22-specific binder (scFv5) 12s:

0VQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREGD TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREGD DALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTI TCRASQSISHFLNWYQQKPGTAPKLLITTASGLGSGVPSRFSGSGSGTDFTLTI TCRASQSISHFLNWYQQKPGTAPKLLITTASGLGSGVPSRFSGSGSGTDFTLTI NSLQPEDLATYYCQQSYTTPLTFGGGTKLEIKR SEQ ID NO: 43 is the nucleic acid sequence of the CD22 CAR LTG2249 (LP-scFv5- CD8TM-41BB-CD3zeta):

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTTGTT FTCCTCCTGATCCCACAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTTGT7 AAACCATCACAGACGCTCTCACTGACCTGTGCCATCTCTGGAGACAGTGT AAACCATCACAGACGCTCTCACTGACCTGTGCCATCTCTGGAGACAGTGT AAGTTCTAACTCAGCCGCGTGGAATTGGATTAGACAATCACCAAGCCGGG AAGTTCTAACTCAGCCGCGTGGAATTGGATTAGACAATCACCAAGCCGGG

100

GACTTGAATGGCTTGGTCGGACGTACTATAGATCTAAGTGGTATAATGAC ACTTGAATGGCTTGGTCGGACGTACTATAGATCTAAGTGGTATAATGA TACGCAGTGTCAGTGAAATCACGGATAACCATAAACCCTGACACCAGCAA TACGCAGTGTCAGTGAAATCACGGATAACCATAAACCCTGACACCAGCAA AAACCAATTTTCTCTTCAGCTTAATTCCGTCACGCCAGAAGATACGGCCGT AAACCAATTTTCTCTTCAGCTTAATTCCGTCACGCCAGAAGATACGGCCGT TTACTACTGTGCGAGGGAAGGTGATGACGCATTGGACATCTGGGGTCAGG TTACTACTGTGCGAGGGAAGGTGATGACGCATTGGACATCTGGGGTCAGG GGACCATGGTGACTGTCTCTTCCGGCGGGGGGGGTAGTGGAGGGGGTGGC TCAGGTGGTGGCGGGTCAGATATACAAATGACACAGAGCCCTAGTAGTCT ICAGGTGGTGGCGGGTCAGATATACAAATGACACAGAGCCCTAGTAGTCT GAGTGCTTCAGTGGGCGACCGCGTAACTATAACCTGTAGAGCATCCCAAA GAGTGCTTCAGTGGGCGACCGCGTAACTATAACCTGTAGAGCATCCCAAA GCATTTCCCACTTCCTTAATTGGTACCAGCAGAAGCCGGGCACAGCGCCC GCATTTCCCACTTCCTTAATTGGTACCAGCAGAAGCCGGGCACAGCGCCC AAACTCCTGATCACCACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCCG AAACTCCTGATCACCACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCCO GTTTAGTGGGTCAGGTAGCGGTACAGATTTCACTCTCACGATAAACTCCCT TCAGCCTGAGGACCTGGCGACATATTACTGTCAACAATCCTATACCACCC FCAGCCTGAGGACCTGGCGACATATTACTGTCAACAATCCTATACCACCC CACTGACATTCGGAGGGGGCACAAAACTGGAGATCAAAGCGGCCGCAAC CACTGACATTCGGAGGGGGCACAAAACTGGAGATCAAAGCGGCCGCAAC TACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCO FACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC AACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCC AACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCC GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCC CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC TGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCAT TGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCAT GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTC GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCC CTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTC CTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTC CGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGC TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGG TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGG ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAG GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAG AAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGC TGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCAT FGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCAT ATGCAAGCACTCCCACCCCGG SEQ ID NO: 44 is the amino acid sequence of the CD22 CAR LTG2249 (LP-scFv5- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQ SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAREGDDALDIWGQGTMVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQSISHFLNWYQQKPGTAPKLLITTA SDIQMTQSPSSLSASVGDRVTITCRASQSISHFLNWYQQKPGTAPKLLITTASG LGSGVPSRFSGSGSGTDFTLTINSLQPEDLATYYCQQSYTTPLTFGGGTKLE LGSGVPSRFSGSGSGTDFTLTINSLQPEDLATYYCQQSYTTPLTFGGGTKLEIK AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAP LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPE] LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS TATKDTYDALHMQALPPR

SEQ ID NO: 45 is the amino acid sequence of the scFv5 (12s) LCDR1:

QSISHF

SEQ ID NO: 46 is the amino acid sequence of the scFv5 (12s) LCDR2:

TAS TAS

101

SEQ ID NO: 47 is the amino acid sequence of the scFv5 (12s) LCDR3:

QQSYTTPLT

SEQ ID NO: 48 is the amino acid sequence of the scFv5 (12s) HCDR1:

GDSVSSNSAA SEQ ID NO: 49 is the amino acid sequence of the scFv5 (12s) HCDR2:

TYYRSKWYN SEQ ID NO: 50 is the amino acid sequence of the scFv5 (12s) HCDR3:

AREGDDALDI SEQ ID NO: 51 is the nucleic acid sequence of the CD22-specific binder (scFv6)

16P3:

CAGATACAGTTGCAGCAGTCAGGTCCAGGACTAGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG IGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTOTG AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCC AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCC AAGAGGTACAACCTGATGATGCTTTAGATATCTGGGGCCAAGGGACAATG AAGAGGTACAACCTGATGATGCTTTAGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG ATCTCTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGG ATCTCTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGO CAGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTG CAGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCT AAGATTTTGCCACTTATTATTGTCAACAGGCTAAAAATTTCCCTTACACTT AAGATTTTGCCACTTATTATTGTCAACAGGCTAAAAATTTCCCTTACACTT TTGGCCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 52 is the amino acid sequence of the CD22-specific binder (scFv6) 16P3:

QIQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRT DIQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR YYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQP YYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQP DDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDKV TITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDFT TITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIK SEQ ID NO: 53 is the nucleic acid sequence of the CD22 CAR LTG2203 (LP-scFv6- CD8TM-41BB-CD3zeta):

ATGTTGTTGCTTGTCACAAGCCTTCTTCTCTGTGAGCTTCCGCACCCGGCTTTCCT ATGTTGTTGCTTGTCACAAGCCTTCTTCTCTGTGAGCTTCCGCACCCGGCTTTCCT GCTGATCCCGCAGATACAGCTTCAGCAGTCCGGCCCCGGTCTGGTAAAGCCGTC GCTGATCCCGCAGATACACCTTCACCAGTCCGGCCCCGGTCTGGTAAAGCCGTCC

CAAACGCTTTCACTCACATGCGCGATCTCTGGTGATTCTGTGTCATCCAACAGCG CAAACGCTTTCACTCACATGCGCGATCTCTGGTGATTCTGTGTCATCCAACAGCG CAGCATGGAATTGGATCCGCCAATCACCCAGTAGAGGCTTGGAGTGGTTGGGCC CAGCATGGAATTGGATCCGCCAATCACCCAGTAGAGGCTTGGAGTGGTTGGGCC GGACTTATTATCGAAGTAAGTGGTACAATGATTATGCAGTCTCAGTTAAATCCAC GGACTTATTATCGAAGTAAGTGGTACAATGATTATGCAGTCTCAGTTAAATCCAG GATCACTATTAACCCAGATACAAGTAAAAACCAGTTCTCATTGCAACTTAATTC GATCACTATTAACCCAGATACAAGTAAAAACCAGTTCTCATTGCAACTTAATTCO GTAACTCCGGAGGACACTGCAGTATATTACTGCGCTCAGGAGGTGCAGCCTGAT GATGCTCTGGACATTTGGGGACAAGGCACGATGGTCACGGTTAGTTCCGGGGGG GGAGGTTCTGGCGGAGGTGGTAGTGGGGGGGGCGGCAGTGACATCCAGATGACA CAGAGTCCCAGCAGCGTGTCTGCGTCAGTCGGGGATAAGGTAACAATTACGTGT CAGAGTCCCAGCAGCGTGTCTGCGTCAGTCGGGGATAAGGTAACAATTACGTGT AGAGCGAGCCAGGACGTTTCCGGGTGGCTGGCGTGGTACCAACAAAAACCCGGT AGAGCGAGCCAGGACGTTTCCGGGTGGCTGGCGTGGTACCAACAAAAACCCGGT CTCGCTCCGCAGTTGCTCATCTCTGGAGCGTCCACCCTTCAGGGAGAGGTGCCTA GCAGATTTTCTGGGTCTGGATCCGGCACGGATTTTACACTTACGATTTCCTCTCT GCAGATTTTCTGGGTCTGGATCCGGCACGGATTTTACACTTACGATTTCCTCTCTT CAACCCGAAGATTTTGCTACTTACTATTGCCAGCAGGCCAAAAACTTCCCGTAC CAACCCGAAGATTTTGCTACTTACTATTGCCAGCAGGCCAAAAACTTCCCGTACA CGTTTGGACAGGGCACAAAGTTGGAAATTAAGGCGGCCGCAACTACCACCCCTG CGTTTGGACAGGGCACAAAGTTGGAAATTAAGGCGGCCGCAACTACCACCCCTG CCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCG CCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGA CCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGA CTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTC CTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTC CTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTT CTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTT ACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG ACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCA GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCA AGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCT4 AGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTA CAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC CAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATO GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATC GGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGG GGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGG ACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCA ACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCA CCCCGG CCCCGG SEQ ID NO: 54 is the amino acid sequence of the CD22 CAR LTG2203 (LP-scFv6- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQIQLQQSGPGLVKPSQTLSLTCAISGDSVSSNS MLLLVTSLLLCELPHPAFLLIPQIQLQQSGPGLVKPSQTLSLTCAISGDSVSSNS AAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQ LNSVTPEDTAVYYCAQEVQPDDALDIWGQGTMVTVSSGGGGSGGGGSGGG LNSVTPEDTAVYYCAQEVQPDDALDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTK ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIVI VAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR EEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGER DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGER RRGKGHDGLYQGLSTATKDTYDALHMQALPPR RRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 55 is the amino acid sequence of the scFv6 (16P3) LCDR1:

QDVSGW SEQ ID NO: 56 is the amino acid sequence of the scFv6 (16P3) LCDR2:

GAS SEQ ID NO: 57 is the amino acid sequence of the scFv6 (16P3) LCDR3:

103

QQAKNFPYT SEQ ID NO: 58 is the amino acid sequence of the scFv6 (16P3) HCDR1:

GDSVSSNSAA SEQ ID NO: 59 is the amino acid sequence of the scFv6 (16P3) HCDR2:

TYYRSKWYN SEQ ID NO: 60 is the amino acid sequence of the scFv6 (16P3) HCDR3:

AQEVQPDDALDI SEQ ID NO: 61 is the nucleic acid sequence of the CD22-specific binder (scFv7)

16P16:

CAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGTGAAACCATCCCAAAG CAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGTGAAACCATCCCAAAC TCTCAGCCTCACGTGTGCTATTTCTGGTGACTCAGTAAGTAGCAATAGCG ICTCAGCCTCACGTGTGCTATTTCTGGTGACTCAGTAAGTAGCAATAGCG TGCTTGGAACTGGATCAGACAATCTCCCTCCAGGGGTCTCGAATGGCTGG TGCTTGGAACTGGATCAGACAATCTCCCTCCAGGGGTCTCGAATGGCTGG GGCGAACCTATTACCGATCTAAATGGTATAACGATTATGCAGTATCCGTG GGCGAACCTATTACCGATCTAAATGGTATAACGATTATGCAGTATCCGTC AAATCCAGGATTACAATCAACCCAGATACGTTCAAGAATCAATTCTCTCTT AAATCCAGGATTACAATCAACCCAGATACGTTCAAGAATCAATTCTCTCTT CAGCTCAACTCCGTAACTCCAGAGGACACTGCGGTATATTATTGCGCCCA CAGCTCAACTCCGTAACTCCAGAGGACACTGCGGTATATTATTGCGCCCA AGAAGTCGAGCCACACGATGCCCTCGATATCTGGGGTCAAGGTACCATGG AGAAGTCGAGCCACACGATGCCCTCGATATCTGGGGTCAAGGTACCATGG TTACAGTTAGTAGTGGGGGTGGGGGAAGCGGGGGCGGTGGGTCCGGTGG ITACAGTTAGTAGTGGGGGTGGGGGAAGCGGGGGCGGTGGGTCCGGTGG CGGGGGTTCAGACATCAAGATGACCCAATCCCCAAGCTCTGTTTCAGCAT CCGTGGGCGATAAGGTAACCATTACATGCAGAGCGAGTCAGGACGTTTCA CCGTGGGCGATAAGGTAACCATTACATGCAGAGCGAGTCAGGACGTTTCA GGGTGGCTGGCTTGGTACCAGCAAAAACCGGGACTCGCACCGCAGCTGTT GGGTGGCTGGCTTGGTACCAGCAAAAACCGGGACTCGCACCGCAGCTGTT GATTTTCGGCGCCAGTACGCTTCAGGGCGAAGTACCGTCCAGGTTCAGTO GATTTTCGGCGCCAGTACGCTTCAGGGCGAAGTACCGTCCAGGTTCAGTG- GGTCAGGTTCTGGCACCGATTTTACGCTCACGATATCCAGTCTCCAACCGG GGTCAGGTTCTGGCACCGATTTTACGCTCACGATATCCAGTCTCCAACCGC AGGATTTTGCTACTTATTACTGCCAGCAGGCTAAGTATTTTCCATACACAT AGGATTTTGCTACTTATTACTGCCAGCAGGCTAAGTATTTTCCATACACAT TTGGCCAGGGGACAAAGTTGGAGATCAAA TTGGCCAGGGGACAAAGTTGGAGATCAAA SEQ ID NO: 62 is the amino acid sequence of the CD22-specific binder (scFv7) 16P16:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTFKNQFSLQLNSVTPEDTAVYYCAQEVE TYYRSKWYNDYAVSVKSRITINPDTFKNQFSLQLNSVTPEDTAVYYCAQEVE PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIKMTQSPSSVSASVGDK PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIKMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK

SEQ ID NO: 63 is the nucleic acid sequence of the CD22 CAR LTG2204 (LP-scFv7- CD8TM-41BB-CD3zeta):

ATGCTGCTTTTGGTAACTTCCCTCCTTTTGTGCGAGCTGCCCCATCCAGCG ATGCTGCTTTTGGTAACTTCCCTCCTTTTGTGCGAGCTGCCCCATCCAGCC TTCCTCCTCATCCCTCAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGTG TTCCTCCTCATCCCTCAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGTC AAACCATCCCAAACTCTCAGCCTCACGTGTGCTATTTCTGGTGACTCAGTA AAACCATCCCAAACTCTCAGCCTCACGTGTGCTATTTCTGGTGACTCAGTA AGTAGCAATAGCGCTGCTTGGAACTGGATCAGACAATCTCCCTCCAGGGG AGTAGCAATAGCGCTGCTTGGAACTGGATCAGACAATCTCCCTCCAGGG TCTCGAATGGCTGGGGCGAACCTATTACCGATCTAAATGGTATAACGATT FCTCGAATGGCTGGGGCGAACCTATTACCGATCTAAATGGTATAACGATT wo 2019/079249 WO PCT/US2018/056011

ATGCAGTATCCGTGAAATCCAGGATTACAATCAACCCAGATACGTTCAAG ATGCAGTATCCGTGAAATCCAGGATTACAATCAACCCAGATACGTTCAAG AATCAATTCTCTCTTCAGCTCAACTCCGTAACTCCAGAGGACACTGCGGTA AATCAATTCTCTCTTCAGCTCAACTCCGTAACTCCAGAGGACACTGCGGTA TATTATTGCGCCCAAGAAGTCGAGCCACACGATGCCCTCGATATCTGGG0 ATTATTGCGCCCAAGAAGTCGAGCCACACGATGCCCTCGATATCTGGGG TCAAGGTACCATGGTTACAGTTAGTAGTGGGGGTGGGGGAAGCGGGGGC CAAGGTACCATGGTTACAGTTAGTAGTGGGGGTGGGGGAAGCGGGGG GGTGGGTCCGGTGGCGGGGGTTCAGACATCAAGATGACCCAATCCCCAAG GGTGGGTCCGGTGGCGGGGGTTCAGACATCAAGATGACCCAATCCCCAAG CTCTGTTTCAGCATCCGTGGGCGATAAGGTAACCATTACATGCAGAGCGA CTCTGTTTCAGCATCCGTGGGCGATAAGGTAACCATTACATGCAGAGCGA GTCAGGACGTTTCAGGGTGGCTGGCTTGGTACCAGCAAAAACCGGGACTO GCACCGCAGCTGTTGATTTTCGGCGCCAGTACGCTTCAGGGCGAAGTACC GCACCGCAGCTGTTGATTTTCGGCGCCAGTACGCTTCAGGGCGAAGTACC GTCCAGGTTCAGTGGGTCAGGTTCTGGCACCGATTTTACGCTCACGATATC GTCCAGGTTCAGTGGGTCAGGTTCTGGCACCGATTTTACGCTCACGATATC CAGTCTCCAACCGGAGGATTTTGCTACTTATTACTGCCAGCAGGCTAAGTA TTTTCCATACACATTTGGCCAGGGGACAAAGTTGGAGATCAAAGCGGCCG ITTTCCATACACATTTGGCCAGGGGACAAAGTTGGAGATCAAAGCGGCCG CAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCA CAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCA AGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGG AGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGG AGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGG AGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGG CCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCO CCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCC TTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCG TTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCG TTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAG TTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAG ATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCAC GGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAAC GAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCA GGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTAC TCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG GCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 64 is the amino acid sequence of the CD22 CAR LTG2204 (LP-scFv7- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQF SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQFSL LNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSG QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLL GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQ GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR SEQ ID NO: 65 is the amino acid sequence of the scFv7 (16P16) LCDR1:

QDVSGW SEQ ID NO: 66 is the amino acid sequence of the scFv7 (16P16) LCDR2:

GAS SEQ ID NO: 67 is the amino acid sequence of the scFv7 (16P16) LCDR3:

QQAKYFPYT wo 2019/079249 WO PCT/US2018/056011

SEQ ID NO: 68 is the amino acid sequence of the scFv7 (16P16) HCDR1:

GDSVSSNSAA SEQ ID NO: 69 is the amino acid sequence of the scFv7 (16P16) HCDR2:

TYYRSKWYN SEQ ID NO: 70 is the amino acid sequence of the scFv7 (16P16) HCDR3:

AQEVEPHDALDI SEQ ID NO: 71 is the nucleic acid sequence of the CD22-specific binder (scFv8)

16P20:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGO TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTC GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCC AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAATG AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAATO GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGAGGCGGTAGCGGTGG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGAGGCGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACGCAGTCTCCATCATCCGTGTCTGCATC TGGCGGATCCGACATCCAGATGACGCAGTCTCCATCATCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAACAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAACAGAAACCAGGGCTAGCCCCTCAGCTCCT ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT GGCCAGGGGACCAAGCTGGAGATCAAA GGCCAGGGGACCAAGCTGGAGATCAAA SEQ ID NO: 72 is the amino acid sequence of the CD22-specific binder (scFv8) 16P20:

9VQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGE TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEV] TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 73 is the nucleic acid sequence of the CD22 CAR LTG2205 (LP-scFv8- CD8TM-41BB-CD3zeta):

ATGCTGCTCCTCGTAACCTCTCTTCTTCTTTGTGAGTTGCCACATCCAGCA ATGCTGCTCCTCGTAACCTCTCTTCTTCTTTGTGAGTTGCCACATCCAGCA TTCTTCTGATACCTCAAGTTCAACTCCAGCAGAGTGGTCCAGGTTTGGTAA ITCTTCTGATACCTCAAGTTCAACTCCAGCAGAGTGGTCCAGGTTTGGTA/ AACCCAGCCAGACTCTCTCATTGACGTGTGCCATATCAGGTGATTCAGTTT AACCCAGCCAGACTCTCTCATTGACGTGTGCCATATCAGGTGATICAGTTT CCTCTAATAGCGCGGCATGGAATTGGATCAGGCAAAGCCCTAGTCGCGGG CCTCTAATAGCGCGGCATGGAATTGGATCAGGCAAAGCCCTAGTCGCGGG CTGGAGTGGCTCGGCCGGACATACTACCGCTCAAAGTGGTACAACGACTA CTGGAGTGGCTCGGCCGGACATACTACCGCTCAAAGTGGTACAACGACT CGCCGTCAGCGTAAAATCTCGGATTACCATTAACCCGGATACTTCCAAAA CGCCGTCAGCGTAAAATCTCGGATTACCATTAACCCGGATACTTCCAAAA wo 2019/079249 WO PCT/US2018/056011

ACCAATTCTCCCTGCAGCTTAACAGTGTCACGCCGGAAGATACGGCCGTT ACCAATTCTCCCTGCAGCTTAACAGTGTCACGCCGGAAGATACGGCCGT TATTACTGCGCACAAGAGGTGGAACCGCACGACGCCCTCGATATCTGGGG TATTACTGCGCACAAGAGGTGGAACCGCACGACGCCCTCGATATCTGGG CCAAGGCACTATGGTGACCGTCAGTAGCGGAGGGGGGGGTTCCGGAGGA GGCGGCTCTGGTGGCGGAGGATCTGATATCCAAATGACCCAATCACCGTC GGCGGCTCTGGTGGCGGAGGATCTGATATCCAAATGACCCAATCACCGTO TTCAGTATCAGCTTCTGTTGGTGACAAAGTTACGATTACCTGTCGAGCGTC TCAGTATCAGCTTCTGTTGGTGACAAAGTTACGATTACCTGTCGAGCGTC ACAGGACGTTTCTGGTTGGTTGGCTTGGTATCAGCAAAAACCAGGGCTTG ACAGGACGTTTCTGGTTGGTTGGCTTGGTATCAGCAAAAACCAGGGCTTG CGCCTCAGTTGCTTATTTTTGGGGCATCTACTTTGCAGGGAGAGGTGCCCT CCGGTTCTCCGGCAGTGGGAGCGGCACCGATTTTACACTTACCATCTCTT CCCGGTTCTCCGGCAGTGGGAGCGGCACCGATTTTACACTTACCATCTCTT CCTTGCAACCCGAAGACTTTGCGACGTACTATTGCCAGCAGGCAAAGTAT CTTGCAACCCGAAGACTTTGCGACGTACTATTGCCAGCAGGCAAAGTAT TTTCCCTACACTTTTGGACAAGGGACTAAACTTGAAATCAAGGCGGCCGC ACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG SEQ ID NO: 74 is the amino acid sequence of the CD22 CAR LTG2205 (LP-scFv8- CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVS MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLID GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCS0 YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR SEQ ID NO: 75 is the amino acid sequence of the scFv8 (16P20) LCDR1:

QDVSGW SEQ ID NO: 76 is the amino acid sequence of the scFv8 (16P20) LCDR2:

GAS SEQ ID NO: 77 is the amino acid sequence of the scFv8 (16P20) LCDR3:

QQAKYFPYT

SEQ ID NO: 78 is the amino acid sequence of the scFv8 (16P20) HCDR1:

GDSVSSNSAA SEQ ID NO: 79 is the amino acid sequence of the scFv8 (16P20) HCDR2:

TYYRSKWYN SEQ ID NO: 80 is the amino acid sequence of the scFv8 (16P20) HCDR3:

AQEVEPHDALDI SEQ ID NO: 81 is the nucleic acid sequence of the CD22-specific binder (scFv9)

16P2:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGA CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTO CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTG TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG FGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTC GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG AAAAGTCGAATAACCATCAACCCAGACACATTCAAGAACCAGTTCTCCC AAAAGTCGAATAACCATCAACCCAGACACATTCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAATG AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTG TGGCGGATCCGACATCAAGATGACCCAGTCTCCATCTTCCGTGTCTGCATO TGGCGGATCCGACATCAAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTG AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT GGCCAGGGGACCAAGCTGGAAATCAAA GGCCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 82 is the amino acid sequence of the CD22-specific binder (scFv9) 16P2:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGE TYYRSKWYNDYAVSVKSRITINPDTFKNQFSLQLNSVTPEDTAVYYCAQEVE TYYRSKWYNDYAVSVKSRITINPDTFKNQFSLQLNSVTPEDTAVYYCAQEVE PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIKMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 83 is the nucleic acid sequence of the CD22 CAR LTG2206 (LP-scFv9- CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAAGTCCAGCTCCAACAATCCGGACCCGGACTTGTT. FCCTGCTTATTCCCCAAGTCCAGCTCCAACAATCCGGACCCGGACTTGTTA AGCCGTCTCAGACGTTGTCACTCACATGCGCCATCAGTGGCGATAGCGTG AGCCGTCTCAGACGTTGTCACTCACATGCGCCATCAGTGGCGATAGCGTG TCCAGCAACAGTGCCGCATGGAATTGGATACGACAGAGCCCTTCCCGAGG TCCAGCAACAGTGCCGCATGGAATTGGATACGACAGAGCCCTTCCCGAGG ATTGGAATGGCTGGGACGAACGTACTATAGGTCCAAGTGGTATAACGACT ATTGGAATGGCTGGGACGAACGTACTATAGGTCCAAGTGGTATAACGACT ACGCGGTGTCAGTTAAATCTCGGATTACTATAAATCCCGACACTTTTAAGA ACGCGGTGTCAGTTAAATCTCGGATTACTATAAATCCCGACACTTTTAAG ATCAGTTTTCCCTGCAACTCAATTCAGTCACACCGGAAGATACGGCAGTG ATCAGTTTTCCCTGCAACTCAATTCAGTCACACCGGAAGATACGGCAGTG

TACTATTGCGCTCAAGAAGTTGAGCCACATGATGCGCTGGATATTTGGGG TACTATTGCGCTCAAGAAGTTGAGCCACATGATGCGCTGGATATTTGGG TCAGGGGACTATGGTGACGGTAAGCAGTGGGGGCGGGGGCAGTGGCGGA TCAGGGGACTATGGTGACGGTAAGCAGTGGGGGCGGGGGCAGTGGCGGA GGTGGCAGCGGGGGCGGTGGAAGCGACATTAAGATGACTCAGTCTCCGTO GGTGGCAGCGGGGGCGGTGGAAGCGACATTAAGATGACTCAGTCTCCGTC TTCAGTTTCCGCCTCCGTAGGGGACAAGGTTACAATTACTTGTCGCGCATO TTCAGTTTCCGCCTCCGTAGGGGACAAGGTTACAATTACTTGTCGCGCATC TCAGGATGTCTCAGGTTGGCTGGCTTGGTATCAACAGAAGCCTGGCCTCG TCAGGATGTCTCAGGTTGGCTGGCTTGGTATCAACAGAAGCCTGGCCTCG CCCCTCAGCTTCTCATATTCGGGGCTAGTACCCTGCAAGGAGAAGTCCCG AGCAGGTTTTCCGGTTCAGGGTCCGGGACAGACTTTACCTTGACCATCAG CTCCCTGCAACCGGAGGACTTCGCGACCTACTATTGTCAACAGGCGAAG CTCCCTGCAACCGGAGGACTTCGCGACCTACTATTGTCAACAGGCGAAGT ACTTCCCCTACACGTTCGGGCAAGGGACTAAGCTCGAAATCAAGGCGGCC ACTTCCCCTACACGTTCGGGCAAGGGACTAAGCTCGAAATCAAGGCGGCC GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGO GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGC AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACO GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA GATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTO CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTC AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA CTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG GCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 84 is the amino acid sequence of the CD222 CARLTG2206 CD22 CAR LTG2206(LP-scFv9- (LP-scFv9- CD8TM-41BB-CD3zeta): CD8TM-41BB-CD3zeta)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQFSI QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSC QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLI GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGI GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR SEQ ID NO: 85 is the amino acid sequence of the scFv9 (16P2) LCDR1:

QDVSGW SEQ ID NO: 86 is the amino acid sequence of the scFv9 (16P2) LCDR2:

GAS GAS SEQ ID NO: 87 is the amino acid sequence of the scFv9 (16P2) LCDR3:

QQAKYFPYT SEQ ID NO: 88 is the amino acid sequence of the scFv9 (16P2) HCDR1:

109

GDSVSSNSAA SEQ ID NO: 89 is the amino acid sequence of the scFv9 (16P2) HCDR2:

TYYRSKWYN SEQ ID NO: 90 is the amino acid sequence of the scFv9 (16P2) HCDR3:

AQEVEPHDALDI SEQ ID NO: 91 is the nucleic acid sequence of the CD22-specific binder (scFv10)

16P6:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTC AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCC GCAGCTGAACTCTGTGACTCCCGAGGATACGGCTGTGTATTACTGTGCCC AAGAGGTACAACCTGATGATGCTTTTGATATCTGGGGCCAAGGGACAATG AAGAGGTACAACCTGATGATGCTTTTGATATCTGGGGCCAAGGGACAATG ATCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG ATCTCTGGTGCATCCACTTTGCAAGGTGGAGTCCCATCAAGGTTCAGCGG ATCTCTGGTGCATCCACTTTGCAAGGTGGAGTCCCATCAAGGTTCAGCGC CAGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTG AGATTTTGCCACTTATTATTGTCAACAGGCTAAAAATTTCCCTTACACTT AAGATTTTGCCACTTATTATTGTCAACAGGCTAAAAATTTCCCTTACACT TTGGTCAGGGGACCAAGCTGGAAATCAAA TTGGTCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 92 is the amino acid sequence of the CD22-specific binder (scFv10) 16P6:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVO PDDAFDIWGQGTMITVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDKY PDDAFDIWGQGTMITVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDKV TITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGGVPSRFSGSGSGTDI TITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIK SEQ ID NO: 93 is the nucleic acid sequence of the CD222 CARLTG2207 CD22 CAR LTG2207(LP- (LP- scFv10-CD8TM-41BB-CD3zeta): scFv10-CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAAGTACAACTCCAGCAATCAGGGCCTGGCCTTGTCA TCCTGCTTATTCCCCAAGTACAACTCCAGCAATCAGGGCCTGGCCTTGTCA AGCCGAGTCAAACCTTGAGTTTGACGTGTGCCATCAGCGGTGACTCTGTC GTTCAAACTCCGCAGCTTGGAACTGGATTCGGCAGTCCCCCTCCAGGGG AGTTCAAACTCCGCAGCTTGGAACTGGATTCGGCAGTCCCCCTCCAGGGC CCTCGAATGGCTTGGACGGACGTACTACAGATCAAAATGGTACAACGACT CCTCGAATGGCTTGGACGGACGTACTACAGATCAAAATGGTACAACGACT ACGCAGTCAGTGTAAAATCAAGGATTACGATAAACCCTGATACGAGTAAA AACCAGTTCTCTCTCCAACTGAACAGCGTCACACCGGAAGATACAGCCGT GTATTACTGTGCTCAGGAAGTGCAACCTGACGACGCATTTGACATCTGGG GTATTACTGTGCTCAGGAAGTGCAACCTGACGACGCATTTGACATCTGGC

110

GTCAGGGCACGATGATCACCGTGAGTAGTGGAGGAGGAGGCAGTGGGC AGGCGGTTCTGGCGGGGGTGGGTCTGATATACAGATGACACAGAGTCC AGGCGGTTCTGGCGGGGGTGGGTCTGATATACAGATGACACAGAGTCCCT CCTCAGTTTCCGCCTCTGTTGGAGATAAGGTGACAATTACATGCAGGGCG TCCCAAGATGTTTCTGGATGGCTCGCATGGTACCAACAGAAGCCAGGACT CCCAAGATGTTTCTGGATGGCTCGCATGGTACCAACAGAAGCCAGGACT CGCCCCTCAGCTCCTCATTAGCGGCGCTAGCACTCTCCAAGGGGGAGTAC CGCCCCTCAGCTCCTCATTAGCGGCGCTAGCACTCTCCAAGGGGGAGTAC CGAGCAGGTTCTCTGGGTCCGGAAGTGGGACGGACTTTACCCTGACAATA TCCTCCCTTCAGCCAGAAGACTTCGCAACCTACTATTGCCAACAGGCGAA TCCTCCCTTCAGCCAGAAGACTTCGCAACCTACTATTGCCAACAGGCGAA AAATTTCCCTTACACGTTCGGCCAAGGAACTAAACTTGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTO TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 94 is the amino acid sequence of the CD22 CAR LTG2207 (LP- scFv10-CD8TM-41BB-CD3zeta)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVS MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFS SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMITVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMITVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY, LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRE WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVOTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 95 is the amino acid sequence of the scFv10 (16P6) LCDR1:

QDVSGW SEQ ID NO: 96 is the amino acid sequence of the scFv10 (16P6) LCDR2:

GAS GAS SEQ ID NO: 97 is the amino acid sequence of the scFv10 scFv 10(16P6) (16P6)LCDR3: LCDR3:

QQAKNFPYT SEQ ID NO: 98 is the amino acid sequence of the scFv10 (16P6) scFvl 10 HCDR1: (16P6) HCDR1:

111

GDSVSSNSAA SEQ ID NO: 99 is the amino acid sequence of the scFv10 (16P6) HCDR2:

TYYRSKWYN SEQ ID NO: 100 is the amino acid sequence of the scFv 10(16P6) scFv10 (16P6)HCDR3: HCDR3:

AQEVQPDDAFDI SEQ ID NO: 101 is the nucleic acid sequence of the CD22-specific binder (scFv11)

16P10:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAG CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG FGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCAGGATGCTTTTGATATCTGGGGCCAAGGGACAATG AAGAGGTAGAACCTCAGGATGCTTTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG ATCTTTGGTGCATCCACTCTGCAAGGTGAAGTCCCATCAAGGTTCAGTGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA GTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT GGCCCGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 102 is the amino acid sequence of the CD22-specific binder (scFv11) 16P10:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PQDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK PQDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGPGTKLEIK

SEQ ID NO: 103 is the nucleic acid sequence of the CD22 CAR LTG2208 (LP- scFv11-CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCI TCCTGCTTATTCCCCAAGTGCAGTTGCAACAGTCTGGACCAGGCCTCGTAA FCCTGCTTATTCCCCAAGTGCAGTTGCAACAGTCTGGACCAGGCCTCGTA/ AACCTTCTCAAACTTTGTCACTCACTTGTGCCATCTCAGGGGACAGTGTCA GTTCCAACAGTGCGGCATGGAATTGGATTAGGCAATCCCCCTCTCGAGGT GTTCCAACAGTGCGGCATGGAATTGGATTAGGCAATCCCCCTCTCGAGGT CTGGAATGGCTTGGGCGGACTTACTACCGAAGTAAGTGGTACAACGATTA TGCAGTTTCTGTAAAATCACGAATCACTATAAATCCGGACACTTCTAAG TGCAGTTTCTGTAAAATCACGAATCACTATAAATCCGGACACTTCTAAGA ATCAGTTCTCTTTGCAGCTTAACTCTGTTACTCCTGAAGACACAGCCGTAT ATTACTGTGCTCAAGAGGTAGAGCCGCAAGATGCCTTCGACATCTGGGGC ATTACTGTGCTCAAGAGGTAGAGCCGCAAGATGCCTTCGACATCTGGGGO CAAGGGACTATGGTGACAGTAAGCTCCGGAGGTGGGGGATCAGGGGGAG CAAGGGACTATGGTGACAGTAAGCTCCGGAGGTGGGGGATCAGGGGGAC

112 wo WO 2019/079249 PCT/US2018/056011 PCT/US2018/056011

GTGGGTCCGGTGGTGGTGGCTCTGACATACAGATGACACAGTCCCCTAG GTGGGTCCGGTGGTGGTGGCTCTGACATACAGATGACACAGTCCCCTAG TCTGTGTCAGCAAGTGTCGGTGACAAGGTTACGATAACGTGCAGGGCCAG ICTGTGTCAGCAAGTGTCGGTGACAAGGTTACGATAACGTGCAGGGCCAC TCAAGATGTGTCAGGATGGTTGGCGTGGTACCAACAGAAACCCGGCTTGG TCAAGATGTGTCAGGATGGTTGGCGTGGTACCAACAGAAACCCGGCTTGE CACCGCAGCTTTTGATATTCGGCGCGTCCACACTCCAAGGCGAAGTGCCTT CACCGCAGCTTTTGATATTCGGCGCGTCCACACTCCAAGGCGAAGTGCCTT CTCGGTTTTCTGGAAGCGGCAGCGGGACGGACTTTACTTTGACAATATCCT CCCTCCAACCCGAGGATTTCGCGACGTATTATTGCCAGCAAGCAAAATAC CCCTCCAACCCGAGGATTTCGCGACGTATTATTGCCAGCAAGCAAAATAC TTCCCATACACCTTCGGGCCTGGGACCAAACTGGAGATCAAAGCGGCCGC TTCCCATACACCTTCGGGCCTGGGACCAAACTGGAGATCAAAGCGGCCGC AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACO GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG SEQ ID NO: 104 is the amino acid sequence of the CD22 CAR LTG2208 (LP- scFv11-CD8TM-41BB-CD3zeta) scFv11-CD8TM-41BB-CD3zeta);

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL NSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGC QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLI ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGPGTKI ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGPGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 105 is the amino acid sequence of the scFv11 (16P10) LCDR1:

PEEGG QDVSGW SEQ ID NO: 106 is the amino acid sequence of the scFv11 (16P10) LCDR2:

GAS SEQ ID NO: 107 is the amino acid sequence of the scFv11 (16P10) LCDR3:

QQAKYFPYT SEQ ID NO: 108 is the amino acid sequence of the scFv11 (16P10) HCDR1:

GDSVSSNSAA

113 wo 2019/079249 WO PCT/US2018/056011

SEQ ID NO: 109 is the amino acid sequence of the scFv11 (16P10) HCDR2:

TYYRSKWYN SEQ ID NO: 110 is the amino acid sequence of the scFv11 (16P10) HCDR3; HCDR3:

AQEVEPQDAFDI SEQ ID NO: 111 is the nucleic acid sequence of the CD22-specific binder (scFv12)

16P17:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCACTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGO CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGC GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGT GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCC' AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCC GCAGTTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGTTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCATGATGCTTTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGC TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTATGCATC TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTATGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG ATCTCTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGG ATCTCTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGG CAGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTG CAGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTG AAGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTT AAGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTT TGGCCAGGGGACCAAGCTGGAAATCAAA TGGCCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 112 is the amino acid sequence of the CD22-specific binder (scFv12) 16P17:

VQLQQSGPGLVKHSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR QVQLQQSGPGLVKHSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PHDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVYASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK

SEQ ID NO: 113 is the nucleic acid sequence of the CD22 CAR LTG2209 (LP- scFv12-CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAGGTACAGCTTCAACAGAGTGGGCCGGGACTGGTO TCCTGCTTATTCCCCAGGTACAGCTTCAACAGAGTGGGCCGGGACTGGTE AAACACTCCCAAACACTTTCTCTGACGTGCGCTATATCAGGTGACTCTGTT TCATCTAATTCTGCTGCGTGGAACTGGATTCGACAATCTCCCAGTCGCGG TCATCTAATTCTGCTGCGTGGAACTGGATTCGACAATCTCCCAGTCGCGGE TTGGAATGGCTGGGACGAACATATTATCGGTCTAAGTGGTATAACGATTA TTGGAATGGCTGGGACGAACATATTATCGGTCTAAGTGGTATAACGATTA TGCTGTATCTGTTAAATCTCGAATTACGATTAATCCTGACACCTCCAAGAA CAGTTCTCCCTCCAGTTGAACTCAGTCACACCGGAAGACACTGCGGTCT CCAGTTCTCCCTCCAGTTGAACTCAGTCACACCGGAAGACACTGCGGTCT ACTATTGCGCTCAAGAAGTCGAGCCACATGATGCATTCGACATCTGGGGC AGGGAACGATGGTCACCGTCAGCAGTGGCGGCGGCGGATCTGGGGGTG CAGGGAACGATGGTCACCGTCAGCAGTGGCGGCGGCGGATCTGGGGGTG GCGGTTCTGGCGGTGGAGGATCAGACATACAAATGACGCAGAGTCCCTCA

AGTGTGTACGCGAGTGTGGGGGATAAGGTAACTATTACGTGCAGAGCGT AGTGTGTACGCGAGTGTGGGGGATAAGGTAACTATTACGTGCAGAGCGTC ACAGGATGTTAGTGGATGGCTTGCCTGGTATCAGCAGAAGCCAGGCCTTO ACAGGATGTTAGTGGATGGCTTGCCTGGTATCAGCAGAAGCCAGGCCTTG CTCCACAGCTCCTTATCAGTGGTGCTTCTACACTTCAGGGCGAGGTTCCGA CTCCACAGCTCCTTATCAGTGGTGCTTCTACACTTCAGGGCGAGGTTCCGA GTAGATTCTCTGGTTCTGGATCTGGTACTGACTTCACTCTTACAATTTCTTC TTTGCAACCAGAAGACTTTGCGACTTATTACTGCCAACAGGCCAAATACT ITTGCAACCAGAAGACTTTGCGACTTATTACTGCCAACAGGCCAAATACTT CCCTTATACATTTGGCCAAGGTACCAAGTTGGAGATAAAGGCGGCCGCAA CCCTTATACATTTGGCCAAGGTACCAAGTTGGAGATAAAGGCGGCCGCAA CTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGC CTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGC CAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGC CAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGC CGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCC CGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCC GCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTA GCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTIA CTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCA TGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTC TGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTC CCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGT CCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAG CCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAG CTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCG CTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCC GACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGA AGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCA AGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCA GAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGG CTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCA CTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCA TATGCAAGCACTCCCACCCCGG TATGCAAGCACTCCCACCCCGG SEQ ID NO: 114 is the amino acid sequence of the CD22 CAR LTG2209 (LP- scFv12-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSJ SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPHDAFDIWGQGTMVTVSSGGGGSGGGGSGGG QLNSVTPEDTAVYYCAQEVEPHDAFDIVWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVYASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG GSDIQMTQSPSSVYASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY, EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRJ PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 115 is the amino acid sequence of the scFv 12(16P17) scFv12 (16P17)LCDR1: LCDR1:

QDVSGW SEQ ID NO: 116 is the amino acid sequence of the scFv12 (16P17) LCDR2:

GAS SEQ ID NO: 117 is the amino acid sequence of the scFv12 (16P17) LCDR3:

QQAKYFPYT SEQ ID NO: 118 is the amino acid sequence of the scFv12 (16P17) HCDR1:

GDSVSSNSAA

115

SEQ ID NO: 119 is the amino acid sequence of the scFv12 (16P17) HCDR2:

TYYRSKWYN SEQ ID NO: 120 is the amino acid sequence of the scFv12 (16P17) HCDR3:

AQEVEPHDAFDI SEQ ID NO: 121 is the nucleic acid sequence of the CD22-specific binder (scFv13)

16P20v2:

CAAGTACAACTTCAACAGTCTGGGCCTGGGCTTGTAAAACCTAGCCAAAC AAGTACAACTTCAACAGTCTGGGCCTGGGCTTGTAAAACCTAGCCAAAC TCTGTCCCTCACGTGCGCGATTTCAGGGGACAGTGTAAGTTCCAACTCAGC CTGTCCCTCACGTGCGCGATTTCAGGGGACAGTGTAAGTTCCAACTCAGC CGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGGGCTCGAATGGCTTG CGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGGGCTCGAATGGCTTG GCCGAACGTACTACAGGAGTAAGTGGTACAACGATTATGCAGTGTCTGTG GCCGAACGTACTACAGGAGTAAGTGGTACAACGATTATGCAGTGTCTGTG AAATCACGGATTACTATCAATCCCGACACGTCCAAGAACCAGTTCTCTCT AAATCACGGATTACTATCAATCCCGACACGTCCAAGAACCAGTTCTCTCT GCAACTCAACTCAGTGACACCAGAGGATACGGCCGTTTACTATTGTGCAC AGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGGTCAGGGCACGATG AGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGGTCAGGGCACGATG GTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGGGGAGGTAGTGGGG GTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGGGGAGGTAGTGGGC GAGGGGGATCTGATATACAGATGACACAAAGCCCGTCATCCGTCAGTGCT GAGGGGGATCTGATATACAGATGACACAAAGCCCGTCATCCGTCAGTGCT TCAGTTGGTGATAAAGTAACCATTACGTGCCGCGCTTCCCAAGACGTTAG CGGATGGTTGGCTTGGTATCAACAAAAACCGGGGTTGGCTCCGCAACTCO CGGATGGTTGGCTTGGTATCAACAAAAACCGGGGTTGGCTCCGCAACTCC TCATATCCGGTGCGAGTACGCTCCAAGGCGAAGTCCCTAGCAGATTTTCC ICATATCCGGTGCGAGTACGCTCCAAGGCGAAGTCCCTAGCAGATTTTCC GGGAGCGGTTCCGGTACAGATTTCACGTTGACCATTAGCTCTCTCCAGCCO GGAGCGGTTCCGGTACAGATTTCACGTTGACCATTAGCTCTCTCCAGCCC GAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAAATTTTCCATATAC GAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAAATTTTCCATATAC TTTGGTCAAGGCACTAAGCTCGAAATCAAA ATTTGGTCAAGGCACTAAGCTCGAAATCAAA SEQ ID NO: 122 is the amino acid sequence of the CD22-specific binder (scFv13) 16P20v2:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGI TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEV TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQ PDDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK PDDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIK

SEQ ID NO: 123 is the nucleic acid sequence of the CD22 CAR LTG2210 (LP- scFv13-CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT TCCTGCTTATTCCCCAAGTACAACTTCAACAGTCTGGGCCTGGGCTTGT TCCTGCTTATTCCCCAAGTACAACTTCAACAGTCTGGGCCTGGGCTTGTAA AACCTAGCCAAACTCTGTCCCTCACGTGCGCGATTTCAGGGGACAGTG AACCTAGCCAAACTCTGTCCCTCACGTGCGCGATTTCAGGGGACAGTGTA AGTTCCAACTCAGCCGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGG AGTTCCAACTCAGCCGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGG GCTCGAATGGCTTGGCCGAACGTACTACAGGAGTAAGTGGTACAACGATT GCTCGAATGGCTTGGCCGAACGTACTACAGGAGTAAGTGGTACAACGAT ATGCAGTGTCTGTGAAATCACGGATTACTATCAATCCCGACACGTCCAAG ATGCAGTGTCTGTGAAATCACGGATTACTATCAATCCCGACACGTCCAAC AACCAGTTCTCTCTGCAACTCAACTCAGTGACACCAGAGGATACGGCCGT AACCAGTTCTCTCTGCAACTCAACTCAGTGACACCAGAGGATACGGCCGT TTACTATTGTGCACAGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGG TTACTATTGTGCACAGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGG TCAGGGCACGATGGTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGG TCAGGGCACGATGGTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGG GGAGGTAGTGGGGGAGGGGGATCTGATATACAGATGACACAAAGCCCG GGAGGTAGTGGGGGAGGGGGATCTGATATACAGATGACACAAAGCCCG CATCCGTCAGTGCTTCAGTTGGTGATAAAGTAACCATTACGTGCCGCGCTT wo 2019/079249 WO PCT/US2018/056011

CCCAAGACGTTAGCGGATGGTTGGCTTGGTATCAACAAAAACCGGGGTTO CCCAAGACGTTAGCGGATGGTTGGCTTGGTATCAACAAAAACCGGGGTTC GCTCCGCAACTCCTCATATCCGGTGCGAGTACGCTCCAAGGCGAAGTCCC TAGCAGATTTTCCGGGAGCGGTTCCGGTACAGATTTCACGTTGACCATTA AGCAGATTTTCCGGGAGCGGTTCCGGTACAGATTICACGTTGACCATTAG CTCTCTCCAGCCCGAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAA CTCTCTCCAGCCCGAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAA ATTTTCCATATACATTTGGTCAAGGCACTAAGCTCGAAATCAAAGCGGCC ATTTTCCATATACATTTGGTCAAGGCACTAAGCTCGAAATCAAAGCGGCC GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGC AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCO GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA GATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA GATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTO CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTO AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA ATCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC CTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG GCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 124 is the amino acid sequence of the CD22 CAR LTG2210 (LP- scFv13-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN AAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL PLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIS GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIS ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQC GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR SEQ ID NO: 125 is the amino acid sequence of the scFv13 (16P20v2) LCDR1:

QDVSGW SEQ ID NO: 126 is the amino acid sequence of the scFv13 (16P20v2) LCDR2:

GAS SEQ ID NO: 127 is the amino acid sequence of the scFv13 (16P20v2) LCDR3:

QQAKNFPYT SEQ ID NO: 128 is the amino acid sequence of the scFv13 (16P20v2) HCDR1 HCDR1:

GDSVSSNSAA SEQ ID NO: 129 is the amino acid sequence of the scFv13 (16P20v2) HCDR2: wo 2019/079249 WO PCT/US2018/056011

TYYRSKWYN SEQ ID NO: 130 is the amino acid sequence of the scFv13 (16P20v2) HCDR3:

AQEVQPDDAFDI SEQ ID NO: 131 is the nucleic acid sequence of the CD22-specific binder (scFv14)

16P1:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGA CCTCTCACTCACCTGTGACATCTCCGGGGACAGTGTCTCTAGCAACAGTGC CCTCTCACTCACCTGTGACATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCO GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGATAGAACCTCATGATGCTTTTGATATCTGGGACCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGTCATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCO TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTC ATCTCTGGTGCATCCTCTTTGCAAGGTGGAGTCCCATCAAGGTTCAGCGGC ATCTCTGGTGCATCCTCTTTGCAAGGTGGAGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT GGCCAGGGGACCAAGCTGGAAATCAAA GGCCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 132 is the amino acid sequence of the CD22-specific binder (scFv14) 16P1:

VQLQQSGPGLVKPSQTLSLTCDISGDSVSSNSAAWNWIRQSPSRGLEWLGR QVQLQQSGPGLVKPSQTLSLTCDISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEIE TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEIEP DAFDIWDQGTMVTVSSGGGGSGGGGSGGGGSVIQMTQSPSSVSASVGDK) HDAFDIWDQGTMVTVSSGGGGSGGGGSGGGGSVIQMTQSPSSVSASVGDKV TITCRASQDVSGWLAWYQQKPGLAPQLLISGASSLQGGVPSRFSGSGSGTDFT STISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK LTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 133 is the nucleic acid sequence of the CD22 CAR LTG2216 (LP- scFv14-CD8TM-41BB-CD3zeta) scFv14-CD8TM-41BB-CD3zeta):

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGATATTAGCGGGGACTCAGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGATATTAGCGGGGACTCAGI CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGO CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGA GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAATCGAACCGCACGACGCCTTCGACATTTGO TGTACTACTGCGCACAAGAAATCGAACCGCACGACGCCTTCGACATTTGG GACCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGTGATCCAGATGACCCAGAGCCCC GCGGTGGATCTGGAGGCGGAGGTTCGGTGATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT wo 2019/079249 WO PCT/US2018/056011

TGGCTCCTCAACTGCTGATCTCCGGCGCCAGCTCACTTCAGGGGGGGGT FGGCTCCTCAACTGCTGATCTCCGGCGCCAGCTCACTTCAGGGGGGGGTG CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCA GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGF CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTO TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGO CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTO AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCC ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCC ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACC ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACE ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 134 is the amino acid sequence of the CD22 CAR LTG2216 (LP- scFv14-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCDISGDSVSS) MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCDISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEIEPHDAFDIWDQGTMVTVSSGGGGSGGGGSGC QLNSVTPEDTAVYYCAQEIEPHDAFDIWDQGTMVTVSSGGGGSGGGGSGGG GSVIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIS GSVIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG ASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK ASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 135 is the amino acid sequence of the scFv14 (16P1) LCDR1:

QDVSGW SEQ ID NO: 136 is the amino acid sequence of the scFv14 (16P1) LCDR2:

GAS SEQ ID NO: 137 is the amino acid sequence of the scFv14 (16P1) LCDR3:

QQAKYFPYT SEQ ID NO: 138 is the amino acid sequence of the scFv14 (16P1) HCDR1 HCDR1:

GDSVSSNSAA SEQ ID NO: 139 is the amino acid sequence of the scFv14 (16P1) HCDR2:

TYYRSKWYN SEQ ID NO: 140 is the amino acid sequence of the scFv14 (16P1) HCDR3:

AQEIEPHDAFDI SEQ ID NO: 141 is the nucleic acid sequence of the CD22-specific binder (scFv15)

16P3v3:

CAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTCAAGCACTCCCAGA CAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTCAAGCACTCCCAGAC TCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAGTCTCGTCCAATTCGO FCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAGTCTCGTCCAATTCGG CGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGGGCCTGGAATGGCTC CGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGGGCCTGGAATGGCTC GGGCGCACTTACTACCGGTCCAAATGGTATAACGACTACGCCGTGTCCGT GGGCGCACTTACTACCGGTCCAAATGGTATAACGACTACGCCGTGTCCGT GAAGTCCCGGATCACCATTAACCCCGACACCTCGAAGAACCAGTTCTCAC GAAGTCCCGGATCACCATTAACCCCGACACCTCGAAGAACCAGTTCTCAC TCCAACTGAACAGCGTGACCCCCGAGGATACCGCGGTGTACTACTGCGCA FCCAACTGAACAGCGTGACCCCCGAGGATACCGCGGTGTACTACTGCGCA AAGAAGTGCAGCCGCAGGACGCCCTGGACATTTGGGGGCAGGGAACGA CAAGAAGTGCAGCCGCAGGACGCCCTGGACATTTGGGGGCAGGGAACGA TGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAGGCGGTGGATCTGGA GGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAGGCGGTGGATCTGGA GGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCCTCCTTCGTGTCCGC GGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCCTCCTTCGTGTCCG ATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGCGTCCCAGGACGTGT ATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGCGTCCCAGGACGTGT CCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCTTGGCTCCTCAACTG CCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCTTGGCTCCTCAACTC CTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGCCATCACGCTTCTCC CTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGCCATCACGCTTCTCC GGATCCGGTTCCGGCACCGACTTCACCCTGACCATCAGCAGCCTCCAGCC TGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAGTACTTCCCCTATAC CTTCGGACAAGGCACTAAGCTGGAAATCAAG CTTCGGACAAGGCACTAAGCTGGAAATCAAG SEQ ID NO: 142 is the amino acid sequence of the CD22-specific binder (scFv15) 16P3v2:

QVQLQQSGPGLVKHSQTLSLACAISGDSVSSNSAAWNWIRQSPSRGLEWLGR QVQLQQSGPGLVKHSQTLSLACAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQ TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVQ PQDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSFVSASVGD) PQDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSFVSASVGDK VIITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDF VITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 143 is the nucleic acid sequence of the CD22 CD222CAR CARLTG2217 LTG2217(LP- (LP- scFv15-CD8TM-41BB-CD3zeta): scFv15-CD8TM-41BB-CD3zeta):

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC. TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCACTCCCAGACTCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAGT AAGCACTCCCAGACTCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGC TGTACTACTGCGCACAAGAAGTGCAGCCGCAGGACGCCCTGGACATTTG TGTACTACTGCGCACAAGAAGTGCAGCCGCAGGACGCCCTGGACATTTGG GGGCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGGCAGGGAACGATGGTCACAGTCTCCTCCGGTGGAGGAGGTTCCGGAC GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCO GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTTCGTGTCCGCATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGCG FCCTTCGTGTCCGCATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGCO TCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCTT ICCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCTT GGCTCCTCAACTGCTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGC GGCTCCTCAACTGCTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGC

120 wo 2019/079249 WO PCT/US2018/056011

CATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATCA GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAG GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAC TACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGGCE ACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGGC CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCO CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGO CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 144 is the amino acid sequence of the CD22 CAR LTG2217 (LP- scFv15-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLACAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSOTLSLACAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQI SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVQPQDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSFVSASVGDKVIITCRASQDVSGWLAWYQQKPGLAPQLLISG GGSDIQMTQSPSFVSASVGDKVITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKI ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 145 is the amino acid sequence of the scFv15 (16P3v2) LCDR1:

QDVSGW SEQ ID NO: 146 is the amino acid sequence of the scFv15 (16P3v2) LCDR2:

GAS SEQ ID NO: 147 is the amino acid sequence of the scFv15 (16P3v2) LCDR3:

QQAKYFPYT SEQ ID NO: 148 is the amino acid sequence of the scFv15 (16P3v2) HCDR1:

GDSVSSNSAA SEQ ID NO: 149 is the amino acid sequence of the scFv15 (16P3v2) HCDR2:

TYYRSKWYN wo 2019/079249 WO PCT/US2018/056011

SEQ ID NO: 150 is the amino acid sequence of the scFv15 (16P3v2) HCDR3:

AQEVQPQDALDI SEQ ID NO: 151 is the nucleic acid sequence of the CD22-specific binder (scFv16)

16P8:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC AGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGO CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATACTGATTATGCAGTATCTGTG AAAAATCGAATAACCATCAACCCAGACACATCCAAGAATCAGTTCTCCCT AAAAATCGAATAACCATCAACCCAGACACATCCAAGAATCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCAGGATGCTTTTGATATCTGGGGCCAAGGGACAATG AAGAGGTAGAACCTCAGGATGCTTTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATO TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGTAGCCTGCAGCCTGA AGTGGATCTGGGACAGATTTTACTCTCACCATCAGTAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT GGCCGGGGGACCAAGCTGGAAATCAAA GGCCGGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 152 is the amino acid sequence of the CD22-specific binder (scFv16) 16P8:

VVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGR TYYRSKWYTDYAVSVKNRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PQDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK PQDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGRGTKLEIK TLTISSLQPEDFATYYCQQAKYFPYTFGRGTKLEIK SEQ ID NO: 153 is the nucleic acid sequence of the CD22 CAR LTG2218 (LP- scFv16-CD8TM-41BB-CD3zeta):

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCAATTAGCGGGGACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATACCGAC TACGCCGTGTCCGTGAAGAATCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCO GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGC7 GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACTCTTCAGGGGGAAGTG FGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACTCTTCAGGGGGAAGTE CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC wo WO 2019/079249 PCT/US2018/056011

AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA GTACTTCCCCTATACCTTCGGAAGAGGCACTAAGCTGGAAATCAAGGCG GTACTTCCCCTATACCTTCGGAAGAGGCACTAAGCTGGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATO GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGO CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCC' CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCO ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 154 is the amino acid sequence of the CD22 CAR LTG2218 (LP- scFv16-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS SAAWNWIRQSPSRGLEWLGRTYYRSKWYTDYAVSVKNRITINPDTSKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYTDYAVSVKNRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGRGTKL ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGRGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRJ WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 155 is the amino acid sequence of the scFv16 (16P8) LCDR1:

QDVSGW SEQ ID NO: 156 is the amino acid sequence of the scFv16 (16P8) LCDR2:

GAS GAS SEQ ID NO: 157 is the amino acid sequence of the scFv16 (16P8) LCDR3:

QQAKYFPYT SEQ ID NO: 158 is the amino acid sequence of the scFv16 (16P8) HCDR1:

GDSVSSNSAA SEQ ID NO: 159 is the amino acid sequence of the scFv16 (16P8) HCDR2:

TYYRSKWYT

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SEQ ID NO: 160 is the amino acid sequence of the scFv16 (16P8) HCDR3:

AQEVEPQDAFDI SEQ ID NO: 161 is the nucleic acid sequence of the CD22-specific binder (scFv17)

16P13:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGA CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCAGGGAACAGTGTCTCTAGCAACAGTGC TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG FGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGC AAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTO AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC AAGAGGTAGAACCTCAAGATGCTTTTGATATCTGGGGCCAAGGGACAATG AAGAGGTAGAACCTCAAGATGCTTTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATO TGGCGGATCCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAGCAGAAACCAGGGCTAGCCCCTCAGCTCCT ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGATTCAGCGGO ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGATTCAGCGGC GGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA GGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTT GGCCAGGGGACCAAGCTGGAAATCAAA GGCCAGGGGACCAAGCTGGAAATCAAA SEQ ID NO: 162 is the amino acid sequence of the CD22-specific binder (scFv17) 16P13:

VQLQOSGPGLVKPSQTLSLTCAISGNSVSSNSAAWNWIRQSPSRGLEWLG TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PQDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGGGSGTD VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGGGSGTD FTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK FTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 163 is the nucleic acid sequence of the CD22 CAR LTG2219 (LP- scFv17-CD8TM-41BB-CD3zeta):

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT0 ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCCATTAGCGGGAACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGG TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAC GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT GGCTCCTCAACTGCTGATCTTTGGCGCCAGCACTCTTCAGGGGGAGGTC TGGCTCCTCAACTGCTGATCTTTGGCGCCAGCACTCTTCAGGGGGAGGTGC CATCACGCTTCTCCGGAGGTGGTTCCGGCACCGACTTCACCCTGACCATCA CATCACGCTTCTCCGGAGGTGGTTCCGGCACCGACTTCACCCTGACCATCA GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAG GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAC

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FACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG TACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGGC CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCO ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 164 is the amino acid sequence of the CD22 CAR LTG2219 (LP- scFv17-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGNSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGNSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSI QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF ASTLQGEVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK ASTLQGEVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY] LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR SEQ ID NO: 165 is the amino acid sequence of the scFv17 (16P13) LCDR1:

QDVSGW SEQ ID NO: 166 is the amino acid sequence of the scFv17 (16P13) LCDR2:

GAS SEQ ID NO: 167 is the amino acid sequence of the scFv17 (16P13) LCDR3:

QQAKYFPYT SEQ ID NO: 168 is the amino acid sequence of the scFv17 (16P13) HCDR1:

GNSVSSNSAA SEQ ID NO: 169 is the amino acid sequence of the scFv17 (16P13) HCDR2:

TYYRSKWYN SEQ ID NO: 170 is the amino acid sequence of the scFv17 (16P13) HCDR3:

AQEVEPQDAFDI SEQ ID NO: 171 is the nucleic acid sequence of the CD22-specific binder (scFv18)

16P15:

CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGAC CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGO CCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTG TGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG FGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTG GAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTE AAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT AAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCT GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCCC GCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCC AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAAT AAGAGGTAGAACCTCATGATGCTCTTGATATCTGGGGCCAAGGGACAATG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG GTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGCGGTGGAGGTAGCGGTGG TGGCGGATCCGACATCCAGATGACGCAGTCTCCATCATCCGTGTCTGCATC TGGCGGATCCGACATCCAGATGACGCAGTCTCCATCATCCGTGTCTGCATC TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG TGTAGGAGACAAAGTCACCATCACTTGTCGGGCGAGTCAGGATGTTAGCG GCTGGTTAGCCTGGTATCAACAGAAACCAGGGCTAGCCCCTCAGCTCCTG GCTGGTTAGCCTGGTATCAACAGAAACCAGGGCTAGCCCCTCAGCTCCTC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC ATCTTTGGTGCATCCACTTTGCAAGGTGAAGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGTGGATCTGGGACAGATTTTACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTT AGATTTTGCCACTTATTATTGTCAACAGGCTAAATATTTCCCTTACACTTTI GGCCAGGGGACCAAGCTGGAGATCAAA GGCCAGGGGACCAAGCTGGAGATCAAA SEQ ID NO: 172 is the amino acid sequence of the CD22-specific binder (scFv18) 16P15:

VQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE TYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAQEVE PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK PHDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDK VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF VTITCRASQDVSGWLAWYQQKPGLAPQLLIFGASTLQGEVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK TLTISSLQPEDFATYYCQQAKYFPYTFGQGTKLEIK SEQ ID NO: 173 is the nucleic acid sequence of the CD22 CAR LTG2220 (LP- scFv18-CD8TM-41BB-CD3zeta):

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGG ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCGATTAGCGGGGACTCAGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCGATTAGCGGGGACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGA GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGC TGTACTACTGCGCACAAGAAGTGGAACCGCACGACGCCCTGGACATTTGG GGTCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGTCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCO TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACACTTCAGGGGGAGGTG TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACACTTCAGGGGGAGGTG CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATO CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCA GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG GTACTTCCCCTATACCTTCGGACAACGCACTAAGCTGGAAATCAAGGCGG

126 wo 2019/079249 WO PCT/US2018/056011

CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATO GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAG CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG- ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 174 is the amino acid sequence of the CD22 CAR LTG2220 (LP- scFv18-CD8TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS) SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGC QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLII GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQG GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR SEQ ID NO: 175 is the amino acid sequence of the scFv18 (16P15) LCDR1:

QDVSGW SEQ ID NO: 176 is the amino acid sequence of the scFv18 (16P15) LCDR2:

GAS SEQ ID NO: 177 is the amino acid sequence of the scFv18 (16P15) LCDR3:

QQAKYFPYT SEQ ID NO: 178 is the amino acid sequence of the scFv18 (16P15) HCDR1:

GDSVSSNSAA SEQ ID NO: 179 is the amino acid sequence of the scFv18 (16P15) HCDR2:

TYYRSKWYN SEQ ID NO: 180 is the amino acid sequence of the scFv18 (16P15) HCDR3: wo WO 2019/079249 PCT/US2018/056011

AQEVEPHDALDI SEQ ID NO: 181 nucleotide sequence of DNA CD8 transmembrane domain

ATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCA ATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCA CCCTTTACTGC

SEQ ID NO: 182 amino acid sequence of CD8 transmembrane domain

IWAPLAGTCGVLLLSLVITLYC IWAPLAGTCGVLLLSLVITLYO

SEQ ID NO: 183 nucleotide sequence of DNA CD8 hinge domain

ACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAG ACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAG CCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAG CCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAG CCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTAC CCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTAC

SEQ ID NO: 184 amino acid sequence of CD8 hinge domain

TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY

SEQ ID NO: 185 amino acid sequence of amino acid numbers 137 to 206 hinge and

transmembrane region of CD8.alpha. (NCBI RefSeq RefSeq:NP.sub.--001759.3) NP.sub.--001759.3)

TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAG TCGVLLLSLVITLYC

SEQ ID NO: 186 nucleotide sequence of DNA signaling domain of 4-1BB

AAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCG AAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCO GCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTG CCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTO AGGAGGAAGAGGGGGGATGCGAACTG AGGAGGAAGAGGGGGGATGCGAACTG

SEQ ID NO: 187 amino acid sequence of signaling domain of 4-1BB

KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

SEQ ID NO: 188 nucleotide sequence of DNA signaling domain of CD3-zeta

CGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCA GCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCA GAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGAC GTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCAC GTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCAC GGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAA GGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAA GATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGG GATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGG GAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGG GGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGG ATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG ATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG

128

SEQ ID NO: 189 amino acid sequence of CD3zeta

PRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR RKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR YDALHMQALPPR SEQ ID NO: 190 nucleotide sequence of leader/signal peptide sequence (LP)

ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTC ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTC TGCTGATTCCG

SEQ ID NO: 191 amino acid sequence of leader/signal peptide sequence (LP)

MLLLVTSLLLCELPHPAFLLIP MLLLVTSLLLCELPHPAFLLIP

SEQ ID NO: 192 nucleotide sequence of ScFv CD19 (FMC63)

GACATTCAGATGACTCAGACCACCTCTTCCTTGTCCGCGTCACTGGGAGAC AGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATCTCCAAGTACCTGAA AGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATCTCCAAGTACCTGAA CTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCTGCTGATCTACCACA CCTCACGCCTGCACAGCGGAGTGCCAAGCAGATTCTCCGGCTCCGGCTCG GGAACCGATTACTCGCTTACCATTAGCAACCTCGAGCAGGAGGACATCGC GGAACCGATTACTCGCTTACCATTAGCAACCTCGAGCAGGAGGACATCGC TACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTACACCTTCGGCGGAG GAACCAAATTGGAAATCACCGGCGGAGGAGGCTCCGGGGGAGGAGGTTC GAACCAAATTGGAAATCACCGGCGGAGGAGGCTCCGGGGGAGGAGGTTC CGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGTCCGGCCCCGGCCTG CGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGTCCGGCCCCGGCCTG GTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCGTGTCGGGAGTGTCC GTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCGTGTCGGGAGTGTCC CTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCGCCGCGGAAGGGCCT CTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCGCCGCGGAAGGGCCT GGAATGGCTGGGTGTCATCTGGGGATCCGAGACTACCTACTACAACTCGG GGAATGGCTGGGTGTCATCTGGGGATCCGAGACTACCTACTACAACTCGC CCCTGAAGTCCCGCCTGACTATCATCAAAGACAACTCGAAGTCCCAGGTC CCCTGAAGTCCCGCCTGACTATCATCAAAGACAACTCGAAGTCCCAGGTC TTTCTGAAGATGAACTCCCTGCAAACTGACGACACCGCCATCTATTACTGT TTTCTGAAGATGAACTCCCTGCAAACTGACGACACCGCCATCTATTACTGT GCTAAGCACTACTACTACGGTGGAAGCTATGCTATGGACTACTGGGGGCA AGGCACTTCGGTGACTGTGTCAAGC AGGCACTTCGGTGACTGTGTCAAGC

SEQ ID NO: 193 amino acid sequence of ScFv CD19 (FMC63)

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHT DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSR LHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT GGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWI GGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWI RQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDD RQPPRKGLEWLGVIWGSETTYYNSALKSRLTIKDNSKSQVFLKMNSLQTDD TAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS TAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS SEQ ID NO: 194 1538 FMC63 CAR nucleotides (LP-FMC63-CD8TM-41BB- CD3zeta)

ATGCTTCTCCTGGTCACCTCCCTGCTCCTCTGCGAACTGCCTCACCCTGCC ATGCTTCTCCTGGTCACCTCCCTGCTCCTCTGCGAACTGCCTCACCCTGCCT TCCTTCTGATTCCTGACATTCAGATGACTCAGACCACCTCTTCCTTGTCCG CGTCACTGGGAGACAGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATC TCCAAGTACCTGAACTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCT TCCAAGTACCTGAACTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCT GCTGATCTACCACACCTCACGCCTGCACAGCGGAGTGCCAAGCAGATTCT GCTGATCTACCACACCTCACGCCTCCACAGCGGAGTGCCAAGCAGATTCT

CCGGCTCCGGCTCGGGAACCGATTACTCGCTTACCATTAGCAACCTCGAG CCGGCTCCGGCTCGGGAACCGATTACTCGCTTACCATTAGCAACCTCGAC CAGGAGGACATCGCTACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTA CAGGAGGACATCGCTACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTA ACCTTCGGCGGAGGAACCAAATTGGAAATCACCGGCGGAGGAGGCTCC CACCTTCGGCGGAGGAACCAAATTGGAAATCACCGGCGGAGGAGGCTCC GGGGGAGGAGGTTCCGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGT GGGGGAGGAGGTTCCGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGT CGGCCCCGGCCTGGTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCO CCGGCCCCGGCCTGGTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCG TGTCGGGAGTGTCCCTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCG CCGCGGAAGGGCCTGGAATGGCTGGGTGTCATCTGGGGATCCGAGACTAC CTACTACAACTCGGCCCTGAAGTCCCGCCTGACTATCATCAAAGACAACT CTACTACAACTCGGCCCTGAAGTCCCGCCTGACTATCATCAAAGACAACT CGAAGTCCCAGGTCTTTCTGAAGATGAACTCCCTGCAAACTGACGACACO CGAAGTCCCAGGTCTTTCTGAAGATGAACTCCCTGCAAACTGACGACAC GCCATCTATTACTGTGCTAAGCACTACTACTACGGTGGAAGCTATGCTATG GCCATCTATTACTGTGCTAAGCACTACTACTACGGTGGAAGCTATGCTAT GACTACTGGGGGCAAGGCACTTCGGTGACTGTGTCAAGCGCGGCCGCAAC GACTACTGGGGGCAAGGCACTTCGGTGACTGTGTCAAGCGCGGCCGCAAC ACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC TACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC AACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCC GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC TGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCAT GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCC GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCC CTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTC CTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGT CGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGC TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCG0 TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGG ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCA0 GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAG AAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGC AAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGC TGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCAT TGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCAT ATGCAAGCACTCCCACCCCGG

SEQ ID NO: 195 is the amino acid sequence of CD19-specific CAR LTG1538 (scFv, FMC63) protein (LP-FMC63-CD8TM-41BB-CD3zeta)

MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKY MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYL NWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIAT NWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATY FCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSO FCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQ SLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTI KKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV IKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAP AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAP LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPI LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS TATKDTYDALHMQALPPR SEQ ID NO: 196 is the nucleic acid sequence of CD22-specifc CAR LTG2200 (scFv, m971 CAR nucleotides (LP-m971-CD8TM-41BB-CD3zeta):

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAGGTACAGCTCCAGCAGAGTGGCCCAGGGCTCGT< TCCTGCTTATTCCCCAGGTACAGCTCCAGCAGAGTGGCCCAGGGCTCGTC AAGCCAAGCCAGACGCTGTCCCTGACTTGTGCAATTTCAGGGGATTCAGT AAGCCAAGCCAGACGCTGTCCCTGACTTGTGCAATTTCAGGGGATTCAGT TTCATCAAATAGCGCGGCGTGGAATTGGATTCGACAATCTCCTTCCCGAG TTCATCAAATAGCGCGGCGTGGAATTGGATTCGACAATCTCCTTCCCGAG GGTTGGAATGGCTTGGACGAACATATTACAGATCCAAATGGTATAACGAC TATGCGGTATCAGTAAAGTCAAGAATAACCATTAACCCCGACACAAGCAA ATGCGGTATCAGTAAAGTCAAGAATAACCATTAACCCCGACACAAGCA

130

GAACCAATTCTCTTTGCAGCTTAACTCTGTCACGCCAGAAGACACGGCAC GAACCAATTCTCTTTGCAGCTTAACTCTGTCACGCCAGAAGACACGGCAG TCTATTATTGCGCTCGCGAGGTAACGGGTGACCTGGAAGACGCTTTTGA0 TCTATTATTGCGCTCGCGAGGTAACGGGTGACCTGGAAGACGCTTTTGAG ATTTGGGGGCAGGGTACGATGGTGACAGTCAGTTCAGGGGGCGGTGGGA ATTTGGGGGCAGGGTACGATGGTGACAGTCAGTTCAGGGGGCGGTGGGA GTGGGGGAGGGGGTAGCGGGGGGGGAGGGTCAGACATTCAGATGACCCA GTCCCCTTCATCCTTGTCTGCCTCCGTCGGTGACAGGGTGACAATAACATG CAGAGCAAGCCAAACAATCTGGAGCTATCTCAACTGGTACCAGCAGCGAC CAGAGCAAGCCAAACAATCTGGAGCTATCTCAACTGGTACCAGCAGCGAC CAGGAAAAGCGCCAAACCTGCTGATTTACGCTGCTTCCTCCCTCCAATCA GGCGTGCCTAGTAGATTTAGCGGTAGGGGCTCCGGCACCGATTTTACGCT CACTATAAGCTCTCTTCAAGCAGAAGATTTTGCGACTTATTACTGCCAGC. CACTATAAGCTCTCTTCAAGCAGAAGATTTTGCGACTTATTACTGCCAGCA TCCTATAGTATACCTCAGACTTTCGGACAGGGTACCAAGTTGGAGATTA GTCCTATAGTATACCTCAGACTTTCGGACAGGGTACCAAGTTGGAGATTA AGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCA AGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCA ACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGC GCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATC ACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGG ACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGG TCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTC AAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGAT AAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGAT ACTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGT GCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGT CAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATC AGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCT AGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCT GGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGG GGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGG AAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGG AAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGG CGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAA GGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCT GGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCT ACGATGCCTTGCATATGCAAGCACTCCCACCCCGG

SEQ ID NO: 197 is the amino acid sequence of LTG2200 CD22-cpecific CAR (LP- m971scFv-CDTN-41BB-CD3zeta) m971scFv-CDTN-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS) SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFS SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVTVSSGGGGSGGGGS QLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVTVSSGGGGSGGGGSG GGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIY GGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIY AASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQG7 AASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSVSIPQTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR SEQ ID NO: 198 is the nucleotide sequence of mesothelin-reactive scFv binding

domain (LTG1904):

GAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT GAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCAT CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCAT GCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTA GCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGT TTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGA TTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAA ITCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAA CAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATTTAT CAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATTTA CGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACC CGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACC

131

WO wo 2019/079249 PCT/US2018/056011

GTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGG ATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACA ATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACA GACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAA GACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAA GCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGT GCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGT AAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTC AAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTC AGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGG AGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGE CTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCG CTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCG GCGGAGGCACCCAGCTGACCGTCCTCGGT GCGGAGGCACCCAGCTGACCGTCCTCGGT SEQ ID NO: 199 is the amino acid sequence of mesothelin-reactive scFv binding domain (LTG1904):

QLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSG EVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGI SWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDLSS SWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDLSSV AGPFNYWGQGTLVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVR ITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASL TITGAQAEDEADYYCNSRDSSGNHLVFGGGTQLTVLG TITGAQAEDEADYYCNSRDSSGNHLVFGGGTQLTVLG SEQ ID NO: 200 is the nucleotide sequence of the mesothelin specific CAR LTG1904 (LP-LTG1904-CD8 TM-41BB-CD3zeta):

ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGG0 ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGC GTTTCTGCTGATTCCGGAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGG TACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCT TTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTG TTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTG GAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGG CTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCC CTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCC TGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTAC TGTGCAAAAGATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCA TGTGCAAAAGATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCA GGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCG GGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCG GTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTG GTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTG TCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCT CAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTG CAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTG TACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGA TACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGA TTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCT CAGGCGGAGGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGG CAGGCGGAGGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGG TAACCATCTGGTATTCGGCGGAGGCACCCAGCTGACCGTCCTCGGTGCGC TAACCATCTGGTATTCGGCGGAGGCACCCAGCTGACCGTCCTCGGTGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC: CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCC CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG

ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG TTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 201 amino acid sequence of the CAR LTG1904 (LP-LTG1904-CD8 TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVQPGGSLRLSCAASGFTFDD MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVQPGGSLRLSCAASGFTFDD YAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQ MNSLRAEDTALYYCAKDLSSVAGPFNYWGQGTLVTVSSGGGGSGGGGSGG GGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIY, GGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYG KNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHLVFGGG TQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFA CDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG CDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLD CSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDK RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD GLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 202 is the nucleotide sequence of CD33-reactive single chain binding

domain VH-4 (LTG1906):

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGG7 CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCAT GAGCTGGGTCCGCCAGGCTCCAAGACAAGGGCTTGAGTGGGTGGCCAAC ATAAAGCAAGATGGAAGTGAGAAATACTATGCGGACTCAGTGAAGGGCC ATAAAGCAAGATGGAAGTGAGAAATACTATGCGGACTCAGTGAAGGGCC GATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATG GATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATG AACAGCCTGAGAGCCGAGGACACAGCCACGTATTACTGTGCGAAAGAAA AACAGCCTGAGAGCCGAGGACACAGCCACGTATTACTGTGCGAAAGAA TGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA ATGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA SEQ ID NO: 203 is the amino acid sequence of CD33-reactive single chain binding domain VH-4 (LTG1906):

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPRQGLEWVANI EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPRQGLEWVANI KQDGSEKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTATYYCAKENY WGQGTLVTVSS SEQ ID NO: 204 is the nucleotide sequence of the CAR LTG1906 (LP-VH4-CD8 TM-41BB-CD3zeta):

ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGC ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGC GTTTCTGCTGATTCCGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGG GTTTCTGCTGATTCCGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGG TACAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCT TCAGTAGCTATGGCATGAGCTGGGTCCGCCAGGCTCCAAGACAAGGGCTT ICAGTAGCTATGGCATGAGCTGGGTCCGCCAGGCTCCAAGACAAGGGCTT GAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGCGG GAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGCGC ACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACG ACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACC CTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACAGCCACGTATTA CTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACAGCCACGTATTA CTGTGCGAAAGAAAATGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCT CTGTGCGAAAGAAAATGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCT CCTCAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCC CCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCC GGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATA TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGG TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGC

133 wo 2019/079249 WO PCT/US2018/056011

GGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATO TGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATC TTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGO TTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGG ATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGC GTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAA GTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAA TCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTG ICAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTG CTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGO CTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGC GGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGAT GGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGA AAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA AAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG SEQ ID NO: 205 is the amino acid sequence of the CAR LTG1906 (LP-VH4-CD8 TM-41BB-CD3zeta):

MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY GMSWVRQAPRQGLEWVANIKQDGSEKYYADSVKGRFTISRDNSKNTLYLQM GMSWVRQAPRQGLEWVANIKQDGSEKYYADSVKGRFTISRDNSKNTLYLQM NSLRAEDTATYYCAKENVDWGQGTLVTVSSAAATTTPAPRPPTPAPTIASQPL NSLRAEDTATYYCAKENVDWGQGTLVTVSSAAATTTPAPRPPTPAPTIASQPL SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGR SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGR KKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQ KKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

134

SequenceListing (3) . txt SequenceListing (3).txt SEQUENCE LISTING SEQUENCE LISTING <110> OF LENTIGEN TECHNOLOGY, THE AMERICA INC DEPARTMENT OF HEALTH AND HUMAN SERVICES, UNITED STATES <110> LENTIGEN TECHNOLOGY, INC THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, UNITED STATES OF AMERICA <120> IMMUNOTHERAPY COMPOSITIONS AND METHODS FOR TREATING CANCER WITH ANTI-CD22 <120> COMPOSITIONS AND METHODS FOR TREATING CANCER WITH ANTI‐CD22 IMMUNOTHERAPY <130> 42449-0017W01 <130> 42449‐0017WO1

<140> <140> <141> <141>

<150> 62/572,926 <150> 62/572,926 <151> 2017-10-16 <151> 2017‐10‐16

<160> 206 <160> 206 <170> PatentIn version 3.5 <170> PatentIn version 3.5

<210> 1 <210> 1 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence <223> polynucleotide Description of Artificial Sequence: Synthetic <220> <220> <223> Description of Artificial Sequence: Synthetic polynucleotide caagtacaac tccagcaaag cgggcctggt ctggtgaagc cgtcacagac gctttcactt <400> 1 <400> 1 caagtacaac tccagcaaag cgggcctggt ctggtgaagc cgtcacagac gctttcactt 60 acgtgtgcga tctccggtga ctccgtgagt tctaatagcg cggcttggaa ctggattagg 60

acgtgtgcga tctccggtga ctccgtgagt tctaatagcg cggcttggaa ctggattagg 120 cagtctccat cccgaggatt ggaatggctc ggcaggactt attatagaag taagtggtac 120

cagtctccat cccgaggatt ggaatggctc ggcaggactt attatagaag taagtggtac 180 aacgattatg cagtctctgt gaaatctcgc atcaccatta acccagacac gtctaagaat 180

aacgattatg cagtctctgt gaaatctcgc atcaccatta acccagacac gtctaagaat 240 cagttcagtc ttcaactcaa ctctgtaacc cccgaagata cagcggtcta ctactgtgct 240

cagttcagtc ttcaactcaa ctctgtaacc cccgaagata cagcggtcta ctactgtgct 300 caggaggtgc aaccccacga tgcttttgat atctggggcc agggtaccat ggttacggtg 300

caggaggtgc aaccccacga tgcttttgat atctggggcc agggtaccat ggttacggtg 360 tcttctgggg gaggggggtc cggtggggga ggatcagggg gtgggggcag cgacatacaa 360

tcttctgggg gaggggggtc cggtggggga ggatcagggg gtgggggcag cgacatacaa 420 atgacgcaat ccccgtcttc tgtttctgcg tctgtcggag ataaagtaac aataacctgt 420

atgacgcaat ccccgtcttc tgtttctgcg tctgtcggag ataaagtaac aataacctgt 480 cgagcgtcac aggacgttag tggctggctt gcgtggtatc agcaaaaacc ggggctcgcc 480

cgagcgtcac aggacgttag tggctggctt gcgtggtatc agcaaaaacc ggggctcgcc 540 540 Page 1 Page 1

SequenceListing (3).txt SequenceListing (3) . txt

ccgcaattgc ttatatttgg agcgagtact cttcagggcg aggtacctag cagattttct 600 ccgcaattgo ttatatttgg agcgagtact cttcagggcg aggtacctag cagattttct 600

gggtccggct caggtacgga cttcaccctg accatatcta gcttgcagcc tgaagatttc 660 gggtccggct caggtacgga cttcaccctg accatatcta gcttgcagcc tgaagatttd 660

gccacctact attgtcaaca ggcgaagaac tttccatata cgttcgggca gggtacgaaa 720 gccacctact attgtcaaca ggcgaagaac tttccatata cgttcgggca gggtacgaaa 720

ttggagataa aa 732 ttggagataa aa 732

<210> 2 <210> 2 <211> 245 <211> 245 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic polypeptide polypeptide

<400> 2 <400> 2 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 20 25 30

Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 35 40 45

Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 50 55 60

Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 70 75 80

Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 85 90 95

Tyr Tyr Cys Ala Gln Glu Val Gln Pro His Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Gln Pro His Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Page 2 Page 2

SequenceListing (3).txt SequenceListing (3) txt Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 130 135 140 130 135 140

Pro Ser Ser Val Ser Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys Pro Ser Ser Val Ser Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys 145 150 155 160 145 150 155 160

Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Ala Trp Tyr Gln Gln Lys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Ala Trp Tyr Gln Gln Lys 165 170 175 165 170 175

Pro Gly Leu Ala Pro Gln Leu Leu Ile Phe Gly Ala Ser Thr Leu Gln Pro Gly Leu Ala Pro Gln Leu Leu Ile Phe Gly Ala Ser Thr Leu Gln 180 185 190 180 185 190

Gly Glu Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Gly Glu Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 195 200 205

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 210 215 220

Cys Gln Gln Ala Lys Asn Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Cys Gln Gln Ala Lys Asn Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 225 230 235 240

Leu Glu Ile Lys Arg Leu Glu Ile Lys Arg 245 245

<210> 3 <210> 3 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic polynucleotide polynucleotide

<400> 3 <400> 3 atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60 atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccago attcctcctg 60

Page 3 Page 3

SequenceListing (3).txt SequenceListing (3) txt atcccacaag tacaactcca gcaaagcggg cctggtctgg tgaagccgtc acagacgctt 120 atcccacaag tacaactcca gcaaagcggg cctggtctgg tgaagccgtc acagacgctt 120

tcacttacgt gtgcgatctc cggtgactcc gtgagttcta atagcgcggc ttggaactgg 180 tcacttacgt gtgcgatctc cggtgactcc gtgagttcta atagcgcggc ttggaactgg 180

attaggcagt ctccatcccg aggattggaa tggctcggca ggacttatta tagaagtaag 240 attaggcagt ctccatcccg aggattggaa tggctcggca ggacttatta tagaagtaag 240

tggtacaacg attatgcagt ctctgtgaaa tctcgcatca ccattaaccc agacacgtct 300 tggtacaacg attatgcagt ctctgtgaaa tctcgcatca ccattaaccc agacacgtct 300

aagaatcagt tcagtcttca actcaactct gtaacccccg aagatacagc ggtctactac 360 aagaatcagt tcagtcttca actcaactct gtaacccccg aagatacago ggtctactac 360

tgtgctcagg aggtgcaacc ccacgatgct tttgatatct ggggccaggg taccatggtt 420 tgtgctcagg aggtgcaacc ccacgatgct tttgatatct ggggccaggg taccatggtt 420

acggtgtctt ctgggggagg ggggtccggt gggggaggat cagggggtgg gggcagcgac 480 acggtgtctt ctgggggagg ggggtccggt gggggaggat cagggggtgg gggcagcgac 480

atacaaatga cgcaatcccc gtcttctgtt tctgcgtctg tcggagataa agtaacaata 540 atacaaatga cgcaatcccc gtcttctgtt tctgcgtctg tcggagataa agtaacaata 540

acctgtcgag cgtcacagga cgttagtggc tggcttgcgt ggtatcagca aaaaccgggg 600 acctgtcgag cgtcacagga cgttagtggc tggcttgcgt ggtatcagca aaaaccgggg 600

ctcgccccgc aattgcttat atttggagcg agtactcttc agggcgaggt acctagcaga 660 ctcgccccgc aattgcttat atttggagcg agtactctto agggcgaggt acctagcaga 660

ttttctgggt ccggctcagg tacggacttc accctgacca tatctagctt gcagcctgaa 720 ttttctgggt ccggctcagg tacggacttc accctgacca tatctagctt gcagcctgaa 720

gatttcgcca cctactattg tcaacaggcg aagaactttc catatacgtt cgggcagggt 780 gatttcgcca cctactattg tcaacaggcg aagaactttd catatacgtt cgggcagggt 780

acgaaattgg agataaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840 acgaaattgg agataaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840

gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900

ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960 ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960

ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020 ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020

ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080

caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 caggaagagg acggatgctc gtgcagatto cctgaggagg aagagggggg atgcgaactg 1140

cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200 cgcgtcaagt tctcacggtc cgccgacgcc cccgcatato aacagggcca gaatcagctc 1200

tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260

cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320 cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320

gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380

aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440 aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440

tacgatgcct tgcatatgca agcactccca ccccgg 1476 tacgatgcct tgcatatgca agcactccca ccccgg 1476

Page 4 Page 4

SequenceListing (3).txt SequenceListing (3) txt

<210> 4 <210> 4 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 4 <400> 4 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Ala Phe Leu Leu Ile Pro Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Ala Phe Leu Leu Ile Pro Gln Val Gln Leu Gln Gln Ser Gly Pro Gly 20 25 30 20 25 30

Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly 35 40 45 35 40 45

Asp Ser Val Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Asp Ser Val Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser 50 55 60 50 55 60

Pro Ser Arg Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Pro Ser Arg Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys 65 70 75 80 70 75 80

Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn 85 90 95 85 90 95

Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr 100 105 110 100 105 110

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro His Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro His 115 120 125 115 120 125

Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 130 135 140 130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Page 5 Page 5

SequenceListing (3).txt SequenceListing (3) txt 145 150 155 160 145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp 165 170 175 165 170 175

Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu 180 185 190 180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Gln Leu Leu Ile Phe Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Gln Leu Leu Ile Phe 195 200 205 195 200 205

Gly Ala Ser Thr Leu Gln Gly Glu Val Pro Ser Arg Phe Ser Gly Ser Gly Ala Ser Thr Leu Gln Gly Glu Val Pro Ser Arg Phe Ser Gly Ser 210 215 220 210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 225 230 235 240 225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Asn Phe Pro Tyr Thr Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Asn Phe Pro Tyr Thr 245 250 255 245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr 260 265 270 260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro 275 280 285 275 280 285

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val 290 295 300 290 295 300

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro 305 310 315 320 305 310 315 320

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu 325 330 335 325 330 335

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Page 6 Page 6

SequenceListing (3).txt SequenceListing (3) txt 340 345 350 340 345 350

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys 355 360 365 355 360 365

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe 370 375 380 370 375 380

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu 385 390 395 400 385 390 395 400

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp 405 410 415 405 410 415

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys 420 425 430 420 425 430

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala 435 440 445 435 440 445

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys 450 455 460 450 455 460

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr 465 470 475 480 465 470 475 480

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 485 490

<210> 5 <210> 5 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic peptide peptide

Page 7 Page 7

SequenceListing (3).txt SequenceListing (3) txt <400> 5 <400> 5 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 6 <210> 6 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 6 <400> 6 Gly Ala Ser Gly Ala Ser 1 1

<210> 7 <210> 7 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 7 <400> 7 Gln Gln Ala Lys Asn Phe Pro Tyr Thr Gln Gln Ala Lys Asn Phe Pro Tyr Thr 1 5 1 5

<210> 8 <210> 8 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 8 <400> 8 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 9 <210> 9

Page 8 Page 8

SequenceListing (3).txt SequenceListing (3) txt <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 9 <400> 9 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 10 <210> 10 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 10 <400> 10 Ala Gln Glu Val Gln Pro His Asp Ala Phe Asp Ile Ala Gln Glu Val Gln Pro His Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 11 <210> 11 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 11 <400> 11 caagtacagc tgcaacaatc tggccctggg cttgtgaaac cctctcagac tttgtccttg caagtacagc tgcaacaatc tggccctggg cttgtgaaac cctctcagac tttgtccttg 60 60

acgtgcgcga taagtggcga ttcagttagt tctaacagcg ccgcttggaa ctggattaga acgtgcgcga taagtggcga ttcagttagt tctaacagcg ccgcttggaa ctggattaga 120 120

cagagcccca gtcggggact cgaatggctt ggccggactt attatcgcag taaatggtat cagagcccca gtcggggact cgaatggctt ggccggactt attatcgcag taaatggtat 180 180

aatgattatg ctgtgagtgt gaaaagtagg atcacaatca accccgatac gagcaagaat aatgattatg ctgtgagtgt gaaaagtagg atcacaatca accccgatac gagcaagaat 240 240

caattctcat tgcaactgaa cagcgtcact cccgaggata cagctgtata ttattgtgca caattctcat tgcaactgaa cagcgtcact cccgaggata cagctgtata ttattgtgca 300 300

agagaaggtg ggtggtatgg cgagatggat gtatggggga aaggaactac ggtaactgtg agagaaggtg ggtggtatgg cgagatggat gtatggggga aaggaactac ggtaactgtg 360 360

Page 9 Page 9

SequenceListing (3).txt SequenceListing (3) . txt

tccagtggcg gaggcggttc aggtggtgga ggctctggag gaggagggtc cgaaatcgtg 420 tccagtggcg gaggcggttc aggtggtgga ggctctggag gaggagggto cgaaatcgtg 420

cttacccagt ctccggctac tctgagcgtt agtccgggtg aaagggcctc actctcttgt 480 cttacccagt ctccggctac tctgagcgtt agtccgggtg aaagggcctc actctcttgt 480

cgagcttcac agtcagtctc ttcctacttg gcttggtatc agcagaagcc aggtcaggcg 540 cgagcttcac agtcagtctc ttcctacttg gcttggtatc agcagaagcc aggtcaggcg 540

ccccgcttgc tcatttacga cgcaagcaca cgagcgacag gcattccaga cagattttct 600 ccccgcttgc tcatttacga cgcaaaccaca cgagcgacag gcattccaga cagattttct 600

ggttctggtt ctggcacgga ctttactctt actataaact cacttgaggc agaggatgct 660 ggttctggtt ctggcacgga ctttactctt actataaact cacttgaggc agaggatgct 660

gcgacttact attgtcacca atcaagctct ctgccttaca cctttgggca aggcaccaaa 720 gcgacttact attgtcacca atcaagctct ctgccttaca cctttgggca aggcaccaaa 720

ctcgaaatca ag 732 ctcgaaatca ag 732

<210> 12 <210> 12 <211> 245 <211> 245 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 12 <400> 12 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 10 Page 10

SequenceListing (3).txt SequenceListing (3) . txt

Tyr Tyr Cys Ala Arg Glu Gly Gly Trp Tyr Gly Glu Met Asp Val Trp Tyr Tyr Cys Ala Arg Glu Gly Gly Trp Tyr Gly Glu Met Asp Val Trp 100 105 110 100 105 110

Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser 130 135 140 130 135 140

Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Ser Leu Ser Cys Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Ser Leu Ser Cys 145 150 155 160 145 150 155 160

Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys 165 170 175 165 170 175

Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Thr Arg Ala Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Thr Arg Ala 180 185 190 180 185 190

Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 195 200 205

Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr 210 215 220 210 215 220

Cys His Gln Ser Ser Ser Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Cys His Gln Ser Ser Ser Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 225 230 235 240

Leu Glu Ile Lys Arg Leu Glu Ile Lys Arg 245 245

<210> 13 <210> 13 <211> 1491 <211> 1491 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<220> <220>

Page 11 Page 11

SequenceListing (3).txt SequenceListing (3) txt <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic polynucleotide polynucleotide

<400> 13 <400> 13 atgctgctgt tggtgacatc acttctgctc tgtgaactcc cccatccagc ctttctgctt 60 atgctgctgt tggtgacatc acttctgctc tgtgaactcc cccatccago ctttctgctt 60

ataccgcaag tacagctgca acaatctggc cctgggcttg tgaaaccctc tcagactttg 120 ataccgcaag tacagctgca acaatctggc cctgggcttg tgaaaccctc tcagactttg 120

tccttgacgt gcgcgataag tggcgattca gttagttcta acagcgccgc ttggaactgg 180 tccttgacgt gcgcgataag tggcgattca gttagttcta acagcgccgc ttggaactgg 180

attagacaga gccccagtcg gggactcgaa tggcttggcc ggacttatta tcgcagtaaa 240 attagacaga gccccagtcg gggactcgaa tggcttggcc ggacttatta tcgcagtaaa 240

tggtataatg attatgctgt gagtgtgaaa agtaggatca caatcaaccc cgatacgagc 300 tggtataatg attatgctgt gagtgtgaaa agtaggatca caatcaacco cgatacgago 300

aagaatcaat tctcattgca actgaacagc gtcactcccg aggatacagc tgtatattat 360 aagaatcaat tctcattgca actgaacago gtcactcccg aggatacago tgtatattat 360

tgtgcaagag aaggtgggtg gtatggcgag atggatgtat gggggaaagg aactacggta 420 tgtgcaagag aaggtgggtg gtatggcgag atggatgtat gggggaaagg aactacggta 420

actgtgtcca gtggcggagg cggttcaggt ggtggaggct ctggaggagg agggtccgaa 480 actgtgtcca gtggcggagg cggttcaggt ggtggaggct ctggaggagg agggtccgaa 480

atcgtgctta cccagtctcc ggctactctg agcgttagtc cgggtgaaag ggcctcactc 540 atcgtgctta cccagtctcc ggctactctg agcgttagtc cgggtgaaag ggcctcactc 540

tcttgtcgag cttcacagtc agtctcttcc tacttggctt ggtatcagca gaagccaggt 600 tcttgtcgag cttcacagtc agtctcttcc tacttggctt ggtatcagca gaagccaggt 600

caggcgcccc gcttgctcat ttacgacgca agcacacgag cgacaggcat tccagacaga 660 caggcgcccc gcttgctcat ttacgacgca agcacacgag cgacaggcat tccagacaga 660

ttttctggtt ctggttctgg cacggacttt actcttacta taaactcact tgaggcagag 720 ttttctggtt ctggttctgg cacggacttt actcttacta taaactcact tgaggcagag 720

gatgctgcga cttactattg tcaccaatca agctctctgc cttacacctt tgggcaaggc 780 gatgctgcga cttactattg tcaccaatca agctctctgc cttacacctt tgggcaaggc 780

accaaactcg aaatcaaggt tacggtatca tctgcggccg caactaccac ccctgcccct 840 accaaactcg aaatcaaggt tacggtatca tctgcggccg caactaccac ccctgcccct 840

cggccgccga ctccggcccc aaccatcgca agccaacccc tctccttgcg ccccgaagct 900 cggccgccga ctccggcccc aaccatcgca agccaacccc tctccttgcg ccccgaagct 900

tgccgcccgg ccgcgggtgg agccgtgcat acccgggggc tggactttgc ctgcgatatc 960 tgccgcccgg ccgcgggtgg agccgtgcat acccgggggc tggactttgc ctgcgatato 960

tacatttggg ccccgctggc cggcacttgc ggcgtgctcc tgctgtcgct ggtcatcacc 1020 tacatttggg ccccgctggc cggcacttgc ggcgtgctcc tgctgtcgct ggtcatcaco 1020

ctttactgca agaggggccg gaagaagctg ctttacatct tcaagcagcc gttcatgcgg 1080 ctttactgca agaggggccg gaagaagctg ctttacatct tcaagcagcc gttcatgcgg 1080

cccgtgcaga cgactcagga agaggacgga tgctcgtgca gattccctga ggaggaagag 1140 cccgtgcaga cgactcagga agaggacgga tgctcgtgca gattccctga ggaggaagag 1140

gggggatgcg aactgcgcgt caagttctca cggtccgccg acgcccccgc atatcaacag 1200 gggggatgcg aactgcgcgt caagttctca cggtccgccg acgcccccgc atatcaacag 1200

ggccagaatc agctctacaa cgagctgaac ctgggaagga gagaggagta cgacgtgctg 1260 ggccagaatc agctctacaa cgagctgaac ctgggaagga gagaggagta cgacgtgctg 1260

gacaagcgac gcggacgcga cccggagatg ggggggaaac cacggcggaa aaaccctcag 1320 gacaagcgac gcggacgcga cccggagatg ggggggaaac cacggcggaa aaaccctcag 1320

Page 12 Page 12

SequenceListing (3).txt SequenceListing (3) . txt gaaggactgt acaacgaact ccagaaagac aagatggcgg aagcctactc agaaatcggg 1380 gaaggactgt acaacgaact ccagaaagac aagatggcgg aagcctacto agaaatcggg 1380

atgaagggag agcggaggag gggaaagggt cacgacgggc tgtaccaggg actgagcacc 1440 atgaagggag agcggaggag gggaaagggt cacgacgggc tgtaccaggg actgagcacc 1440

gccactaagg atacctacga tgccttgcat atgcaagcac tcccaccccg g 1491 gccactaagg atacctacga tgccttgcat atgcaagcad tcccaccccg g 1491

<210> 14 <210> 14 <211> 497 <211> 497 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 14 <400> 14 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Gly Trp Tyr Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Gly Trp Tyr 115 120 125 115 120 125

Page 13 Page 13

SequenceListing (3).txt SequenceListing (3) . txt

Gly Glu Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Glu Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 130 135 140 130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 145 150 155 160 145 150 155 160

Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu 165 170 175 165 170 175

Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu 180 185 190 180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 195 200 205 195 200 205

Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser 210 215 220 210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu 225 230 235 240 225 230 235 240

Asp Ala Ala Thr Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Tyr Thr Asp Ala Ala Thr Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Tyr Thr 245 250 255 245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Val Thr Val Ser Ser Ala Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Val Thr Val Ser Ser Ala 260 265 270 260 265 270

Ala Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ala Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 275 280 285 275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 290 295 300 290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 305 310 315 320 305 310 315 320

Page 14 Page 14

SequenceListing (3).txt SequenceListing (3) . txt

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 325 330 335 325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr 340 345 350 340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 355 360 365 355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 370 375 380 370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 385 390 395 400 385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 405 410 415 405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 420 425 430 420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 435 440 445 435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 450 455 460 450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 465 470 475 480 465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 485 490 495 485 490 495

Arg Arg

Page 15 Page 15

SequenceListing (3).txt SequenceListing (3) txt

<210> 15 <210> 15 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 15 <400> 15 Gln Ser Val Ser Ser Tyr Gln Ser Val Ser Ser Tyr 1 5 1 5

<210> 16 <210> 16 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 16 <400> 16 Asp Ala Ser Asp Ala Ser 1 1

<210> 17 <210> 17 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 17 <400> 17 His Gln Ser Ser Ser Leu Pro Tyr Thr His Gln Ser Ser Ser Leu Pro Tyr Thr 1 5 1 5

<210> 18 <210> 18 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 16 Page 16

SequenceListing (3).txt SequenceListing (3) . txt <220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic peptide peptide

<400> 18 <400> 18 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 19 <210> 19 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 19 <400> 19 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 20 <210> 20 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 20 <400> 20 Ala Arg Glu Gly Gly Trp Tyr Gly Glu Met Asp Val Ala Arg Glu Gly Gly Trp Tyr Gly Glu Met Asp Val 1 5 10 1 5 10

<210> 21 <210> 21 <211> 744 <211> 744 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 21 <400> 21 caagtacagc tccaacagag tggacctggt ctcgttaagc cgtcccaaac actgtctttg 60 caagtacago tccaacagag tggacctggt ctcgttaagc cgtcccaaac actgtctttg 60

Page 17 Page 17

SequenceListing (3).txt SequenceListing (3) . txt

acgtgcgcta ttagtggcga cagcgtatca tccaattctg ctgcttggaa ctggattaga 120 acgtgcgcta ttagtggcga cagcgtatca tccaattctg ctgcttggaa ctggattaga 120

cagtcaccgt ccagaggctt ggaatggctg ggcaggacgt actaccgctc aaaatggtat 180 cagtcaccgt ccagaggctt ggaatggctg ggcaggacgt actaccgctc aaaatggtat 180

aacgattacg cggttagtgt caaatccagg attaccatta accctgacac aagtaagaat 240 aacgattacg cggttagtgt caaatccagg attaccatta accctgacac aagtaagaat 240

cagttttctc ttcagctgaa ttccctgact cctgaggata cggccgttta ctactgtgcc 300 cagttttctc ttcagctgaa ttccctgact cctgaggata cggccgttta ctactgtgcc 300

cgagaacacc agaatgaggc ggcttttgat atttgggggc aaggaacaat ggtcacagtt 360 cgagaacacc agaatgaggc ggcttttgat atttgggggc aaggaacaat ggtcacagtt 360

agcagtgggg ggggtggctc cgggggaggt ggttccggcg gcggtggttc tcaatccgtc 420 agcagtgggg ggggtggctc cgggggaggt ggttccggcg gcggtggttc tcaatccgtc 420

ctgacacaac ctccctcagc gagcgggact cccggtcaaa gggtgaccat ctcttgttct 480 ctgacacaac ctccctcago gagcgggact cccggtcaaa gggtgaccat ctcttgttct 480

gggggaggta gtaacatcgg gacaaatact gcgtcctggt atcagcaact ccctgggacc 540 gggggaggta gtaacatcgg gacaaatact gcgtcctggt atcagcaact ccctgggaco 540

gctcccaagt tgttgatata tcgcaatacg caacgaccta gtgggatacc tgatagattc 600 gctcccaagt tgttgatata tcgcaatacg caacgaccta gtgggatacc tgatagatto 600

agcggaagca aaagtggtac gagtgcgtct ttggcaatat ctggcctcca gtccgaggac 660 agcggaagca aaagtggtac gagtgcgtct ttggcaatat ctggcctcca gtccgaggad 660

gaagcggatt actattgtgc ggcctgggat gactcactga atggttatgt gttcggtgca 720 gaagcggatt actattgtgc ggcctgggat gactcactga atggttatgt gttcggtgca 720

ggtactcaac tcaccgtact tggt 744 ggtactcaac tcaccgtact tggt 744

<210> 22 <210> 22 <211> 248 <211> 248 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 22 <400> 22 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 18 Page 18

SequenceListing (3).txt SequenceListing (3) . txt Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 50 55 60

Gln Phe Ser Leu Gln Leu Asn Ser Leu Thr Pro Glu Asp Thr Ala Val Gln Phe Ser Leu Gln Leu Asn Ser Leu Thr Pro Glu Asp Thr Ala Val 85 90 95 85 90 95

Tyr Tyr Cys Ala Arg Glu His Gln Asn Glu Ala Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Arg Glu His Gln Asn Glu Ala Ala Phe Asp Ile Trp 100 105 110 100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro 130 135 140 130 135 140

Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser 145 150 155 160 145 150 155 160

Gly Gly Gly Ser Asn Ile Gly Thr Asn Thr Ala Ser Trp Tyr Gln Gln Gly Gly Gly Ser Asn Ile Gly Thr Asn Thr Ala Ser Trp Tyr Gln Gln 165 170 175 165 170 175

Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asn Thr Gln Arg Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asn Thr Gln Arg 180 185 190 180 185 190

Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 195 200 205 195 200 205

Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr 210 215 220 210 215 220

Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val Phe Gly Ala Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val Phe Gly Ala 225 230 235 240 225 230 235 240

Page 19 Page 19

SequenceListing (3).txt SequenceListing (3) txt Gly Thr Gln Leu Thr Val Leu Gly Gly Thr Gln Leu Thr Val Leu Gly 245 245

<210> 23 <210> 23 <211> 1488 <211> 1488 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 23 <400> 23 atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60 atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60

atcccacaag tacagctcca acagagtgga cctggtctcg ttaagccgtc ccaaacactg 120 atcccacaag tacagctcca acagagtgga cctggtctcg ttaagccgtc ccaaacactg 120

tctttgacgt gcgctattag tggcgacagc gtatcatcca attctgctgc ttggaactgg 180 tctttgacgt gcgctattag tggcgacagc gtatcatcca attctgctgc ttggaactgg 180

attagacagt caccgtccag aggcttggaa tggctgggca ggacgtacta ccgctcaaaa 240 attagacagt caccgtccag aggcttggaa tggctgggca ggacgtacta ccgctcaaaa 240

tggtataacg attacgcggt tagtgtcaaa tccaggatta ccattaaccc tgacacaagt 300 tggtataacg attacgcggt tagtgtcaaa tccaggatta ccattaaccc tgacacaagt 300

aagaatcagt tttctcttca gctgaattcc ctgactcctg aggatacggc cgtttactac 360 aagaatcagt tttctcttca gctgaattcc ctgactcctg aggatacggc cgtttactac 360

tgtgcccgag aacaccagaa tgaggcggct tttgatattt gggggcaagg aacaatggtc 420 tgtgcccgag aacaccagaa tgaggcggct tttgatattt gggggcaagg aacaatggtc 420

acagttagca gtgggggggg tggctccggg ggaggtggtt ccggcggcgg tggttctcaa 480 acagttagca gtgggggggg tggctccggg ggaggtggtt ccggcggcgg tggttctcaa 480

tccgtcctga cacaacctcc ctcagcgagc gggactcccg gtcaaagggt gaccatctct 540 tccgtcctga cacaacctcc ctcagcgago gggactcccg gtcaaagggt gaccatctct 540

tgttctgggg gaggtagtaa catcgggaca aatactgcgt cctggtatca gcaactccct 600 tgttctgggg gaggtagtaa catcgggaca aatactgcgt cctggtatca gcaactccct 600

gggaccgctc ccaagttgtt gatatatcgc aatacgcaac gacctagtgg gatacctgat 660 gggaccgctc ccaagttgtt gatatatcgc aatacgcaac gacctagtgg gatacctgat 660

agattcagcg gaagcaaaag tggtacgagt gcgtctttgg caatatctgg cctccagtcc 720 agattcagcg gaagcaaaag tggtacgagt gcgtctttgg caatatctgg cctccagtcc 720

gaggacgaag cggattacta ttgtgcggcc tgggatgact cactgaatgg ttatgtgttc 780 gaggacgaag cggattacta ttgtgcggcc tgggatgact cactgaatgg ttatgtgttc 780

ggtgcaggta ctcaactcac cgtacttggt gcggccgcaa ctaccacccc tgcccctcgg 840 ggtgcaggta ctcaactcac cgtacttggt gcggccgcaa ctaccacccc tgcccctcgg 840

ccgccgactc cggccccaac catcgcaagc caacccctct ccttgcgccc cgaagcttgc 900 ccgccgactc cggccccaac catcgcaagc caacccctct ccttgcgccc cgaagcttgc 900

cgcccggccg cgggtggagc cgtgcatacc cgggggctgg actttgcctg cgatatctac 960 cgcccggccg cgggtggagc cgtgcatacc cgggggctgg actttgcctg cgatatctac 960

atttgggccc cgctggccgg cacttgcggc gtgctcctgc tgtcgctggt catcaccctt 1020 atttgggccc cgctggccgg cacttgcggc gtgctcctgc tgtcgctggt catcaccctt 1020

Page 20 Page 20

SequenceListing (3).txt SequenceListing (3) . txt tactgcaaga ggggccggaa gaagctgctt tacatcttca agcagccgtt catgcggccc 1080 tactgcaaga ggggccggaa gaagctgctt tacatcttca agcagccgtt catgcggccc 1080

gtgcagacga ctcaggaaga ggacggatgc tcgtgcagat tccctgagga ggaagagggg 1140 gtgcagacga ctcaggaaga ggacggatgo tcgtgcagat tccctgagga ggaagagggg 1140

ggatgcgaac tgcgcgtcaa gttctcacgg tccgccgacg cccccgcata tcaacagggc 1200 ggatgcgaac tgcgcgtcaa gttctcacgg tccgccgacg cccccgcata tcaacagggo 1200

cagaatcagc tctacaacga gctgaacctg ggaaggagag aggagtacga cgtgctggac 1260 cagaatcagc tctacaacga gctgaacctg ggaaggagag aggagtacga cgtgctggad 1260

aagcgacgcg gacgcgaccc ggagatgggg gggaaaccac ggcggaaaaa ccctcaggaa 1320 aagcgacgcg gacgcgacco ggagatgggg gggaaaccao ggcggaaaaa ccctcaggaa 1320

ggactgtaca acgaactcca gaaagacaag atggcggaag cctactcaga aatcgggatg 1380 ggactgtaca acgaactcca gaaagacaag atggcggaag cctactcaga aatcgggatg 1380

aagggagagc ggaggagggg aaagggtcac gacgggctgt accagggact gagcaccgcc 1440 aagggagago ggaggagggg aaagggtcad gacgggctgt accagggact gagcaccgco 1440

actaaggata cctacgatgc cttgcatatg caagcactcc caccccgg 1488 actaaggata cctacgatgo cttgcatatg caagcactco caccccgg 1488

<210> 24 <210> 24 <211> 496 <211> 496 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 24 <400> 24 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Page 21 Page 21

SequenceListing (3).txt SequenceListing (3) . txt 85 90 95 85 90 95

Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Leu Thr Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Leu Thr 100 105 110 100 105 110

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu His Gln Asn Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu His Gln Asn Glu 115 120 125 115 120 125

Ala Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 130 135 140 130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 145 150 155 160 145 150 155 160

Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg 165 170 175 165 170 175

Val Thr Ile Ser Cys Ser Gly Gly Gly Ser Asn Ile Gly Thr Asn Thr Val Thr Ile Ser Cys Ser Gly Gly Gly Ser Asn Ile Gly Thr Asn Thr 180 185 190 180 185 190

Ala Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Ala Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile 195 200 205 195 200 205

Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 210 215 220 210 215 220

Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser 225 230 235 240 225 230 235 240

Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 245 250 255 245 250 255

Gly Tyr Val Phe Gly Ala Gly Thr Gln Leu Thr Val Leu Gly Ala Ala Gly Tyr Val Phe Gly Ala Gly Thr Gln Leu Thr Val Leu Gly Ala Ala 260 265 270 260 265 270

Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Page 22 Page 22

SequenceListing (3).txt SequenceListing (3) txt 275 280 285 275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala 290 295 300 290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 305 310 315 320 305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 325 330 335 325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile 340 345 350 340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp 355 360 365 355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 370 375 380 370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 385 390 395 400 385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 405 410 415 405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 420 425 430 420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 435 440 445 435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 450 455 460 450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Page 23 Page 23

SequenceListing (3).txt SequenceListing (3) . txt 465 470 475 480 465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 495 485 490 495

<210> 25 <210> 25 <211> 8 <211> 8 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 25 <400> 25 Gly Ser Asn Ile Gly Thr Asn Thr Gly Ser Asn Ile Gly Thr Asn Thr 1 5 1 5

<210> 26 <210> 26 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 26 <400> 26 Arg Asn Thr Arg Asn Thr 1 1

<210> 27 <210> 27 <211> 11 <211> 11 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 27 <400> 27 Ala Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val Ala Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val 1 5 10 1 5 10

Page 24 Page 24

SequenceListing (3).txt SequenceListing (3) txt

<210> 28 <210> 28 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 28 <400> 28 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 29 <210> 29 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 29 <400> 29 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 30 <210> 30 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 30 <400> 30 Ala Arg Glu His Gln Asn Glu Ala Ala Phe Asp Ile Ala Arg Glu His Gln Asn Glu Ala Ala Phe Asp Ile 1 5 10 1 5 10

<210> 31 <210> 31 <211> 729 <211> 729 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 25 Page 25

SequenceListing (3).txt SequenceListing (3) . txt <220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic polynucleotide polynucleotide

<400> 31 <400> 31 caagtccagt tgcaacagtc cgggccaggt ctggttaagc catcccaaac tctgagtttg 60 caagtccagt tgcaacagto cgggccaggt ctggttaago catcccaaac tctgagtttg 60

acgtgcgcta ttagcggaga ttccgtgtcc agcaattctg caacctggaa ttggatccgg 120 acgtgcgcta ttagcggaga ttccgtgtcc agcaattctg caacctggaa ttggatccgg 120

cagagtccga gtggcggttt ggaatggctc ggacgcactt actacaggag caaatggtac 180 cagagtccga gtggcggttt ggaatggctc ggacgcactt actacaggag caaatggtac 180

gatgattatg ctgtttctgt gcgctctcga atcaccatga atcctgatac ttctaagaac 240 gatgattatg ctgtttctgt gcgctctcga atcaccatga atcctgatac ttctaagaac 240

caattttctt tgcagttgaa ctccgtcacg cctgaagata ctgcggtcta ctattgcgca 300 caattttctt tgcagttgaa ctccgtcacg cctgaagata ctgcggtcta ctattgcgca 300

cgcgaaggcg tagccggcga ttttgattac tgggggcaag gaacattggt cacggtctcc 360 cgcgaaggcg tagccggcga ttttgattac tgggggcaag gaacattggt cacggtctco 360

tctggtggag gaggatcagg aggcgggggt tcaggtggag gtgggagcga tattcaactt 420 tctggtggag gaggatcagg aggcgggggt tcaggtggag gtgggagcga tattcaactt 420

acgcagtctc cgagcagtct ttctgcttcc gtgggagacc gagtgacgat tacttgtagg 480 acgcagtctc cgagcagtct ttctgcttcc gtgggagacc gagtgacgat tacttgtagg 480

gcatctcagt caataagttc ctatcttaac tggtatcagc agaagcctgg aaaggctcca 540 gcatctcagt caataagttc ctatcttaac tggtatcago agaagcctgg aaaggctcca 540

aaacttctta tttatgccgc atcctcattg caatccggcg tgccttcccg attttccgga 600 aaacttctta tttatgccgc atcctcattg caatccggcg tgccttcccg attttccgga 600

tctggctcag gcactgactt taccttgact attagttccc ttcaaccaga agattttgct 660 tctggctcag gcactgactt taccttgact attagttccc ttcaaccaga agattttgct 660

acctattact gccaacaatc atacagtacc ccatatacat tcggccaagg cacgaaattg 720 acctattact gccaacaatc atacagtacc ccatatacat tcggccaagg cacgaaattg 720

gagattaaa 729 gagattaaa 729

<210> 32 <210> 32 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 32 <400> 32 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 26 Page 26

SequenceListing (3).txt SequenceListing (3) txt

Ser Ala Thr Trp Asn Trp Ile Arg Gln Ser Pro Ser Gly Gly Leu Glu Ser Ala Thr Trp Asn Trp Ile Arg Gln Ser Pro Ser Gly Gly Leu Glu 35 40 45 35 40 45

Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asp Asp Tyr Ala Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asp Asp Tyr Ala 50 55 60 50 55 60

Val Ser Val Arg Ser Arg Ile Thr Met Asn Pro Asp Thr Ser Lys Asn Val Ser Val Arg Ser Arg Ile Thr Met Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 70 75 80

Tyr Tyr Cys Ala Arg Glu Gly Val Ala Gly Asp Phe Asp Tyr Trp Gly Tyr Tyr Cys Ala Arg Glu Gly Val Ala Gly Asp Phe Asp Tyr Trp Gly 100 105 110 100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 115 120 125

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro 130 135 140 130 135 140

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 145 150 155 160

Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 165 170 175

Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 180 185 190

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 195 200 205

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 210 215 220

Page 27 Page 27

SequenceListing (3).txt SequenceListing (3) . txt

Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu 225 230 235 240 225 230 235 240

Glu Ile Lys Arg Glu Ile Lys Arg

<210> 33 <210> 33 <211> 1473 <211> 1473 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 33 <400> 33 atgcttctcc tggtgacaag ccttctgctc tgtgagttad cacacccago attcctcctg atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60 60

atcccacaag tccagttgca acagtccggg ccaggtctgg ttaagccatc ccaaactctg atcccacaag tccagttgca acagtccggg ccaggtctgg ttaagccatc ccaaactctg 120 120

agtttgacgt gcgctattag cggagattco gtgtccagca attctgcaac ctggaattgg agtttgacgt gcgctattag cggagattcc gtgtccagca attctgcaac ctggaattgg 180 180

atccggcaga gtccgagtgg cggtttggaa tggctcggac gcacttacta caggagcaaa atccggcaga gtccgagtgg cggtttggaa tggctcggac gcacttacta caggagcaaa 240 240

tggtacgatg attatgctgt ttctgtgcgc tctcgaatca ccatgaatco tgatacttct tggtacgatg attatgctgt ttctgtgcgc tctcgaatca ccatgaatcc tgatacttct 300 300

aagaaccaat tttctttgca gttgaactcc gtcacgcctg aagatactgo ggtctactat aagaaccaat tttctttgca gttgaactcc gtcacgcctg aagatactgc ggtctactat 360 360

tgcgcacgcg aaggcgtagc cggcgatttt gattactggg ggcaaaggaao attggtcacg tgcgcacgcg aaggcgtagc cggcgatttt gattactggg ggcaaggaac attggtcacg 420 420 gtctcctctg gtggaggagg atcaggaggc gggggttcag gtggaggtgg gagcgatatt gtctcctctg gtggaggagg atcaggaggc gggggttcag gtggaggtgg gagcgatatt 480 480 caacttacgc agtctccgag cagtctttct gcttccgtgg gagaccgagt gacgattact caacttacgc agtctccgag cagtctttct gcttccgtgg gagaccgagt gacgattact 540 540

tgtagggcat ctcagtcaat aagttcctat cttaactggt atcagcagaa gcctggaaag tgtagggcat ctcagtcaat aagttcctat cttaactggt atcagcagaa gcctggaaag 600 600

gctccaaaac ttcttattta tgccgcatcc tcattgcaat ccggcgtgcc ttcccgattt gctccaaaac ttcttattta tgccgcatcc tcattgcaat ccggcgtgcc ttcccgattt 660 660

tccggatctg gctcaggcac tgactttacc ttgactatta gttcccttca accagaagat tccggatctg gctcaggcac tgactttacc ttgactatta gttcccttca accagaagat 720 720

tttgctacct attactgcca acaatcatac agtaccccat atacattcgg ccaaggcacg tttgctacct attactgcca acaatcatac agtaccccat atacattcgg ccaaggcacg 780 780

aaattggaga ttaaagcggc cgcaactacc acccctgccc ctcggccgcc gactccggcc aaattggaga ttaaagcggc cgcaactacc acccctgccc ctcggccgcc gactccggcc 840 840

Page 28 Page 28

SequenceListing (3).txt SequenceListing (3) . txt ccaaccatcg caagccaacc cctctccttg cgccccgaag cttgccgccc ggccgcgggt 900 ccaaccatcg caagccaaco cctctccttg cgccccgaag cttgccgccc ggccgcgggt 900

ggagccgtgc atacccgggg gctggacttt gcctgcgata tctacatttg ggccccgctg 960 ggagccgtgc atacccgggg gctggacttt gcctgcgata tctacatttg ggccccgctg 960

gccggcactt gcggcgtgct cctgctgtcg ctggtcatca ccctttactg caagaggggc 1020 gccggcactt gcggcgtgct cctgctgtcg ctggtcatca ccctttactg caagaggggo 1020

cggaagaagc tgctttacat cttcaagcag ccgttcatgc ggcccgtgca gacgactcag 1080 cggaagaago tgctttacat cttcaagcag ccgttcatgo ggcccgtgca gacgactcag 1080

gaagaggacg gatgctcgtg cagattccct gaggaggaag aggggggatg cgaactgcgc 1140 gaagaggacg gatgctcgtg cagattccct gaggaggaag aggggggatg cgaactgcgc 1140

gtcaagttct cacggtccgc cgacgccccc gcatatcaac agggccagaa tcagctctac 1200 gtcaagttct cacggtccgc cgacgcccco gcatatcaac agggccagaa tcagctctad 1200

aacgagctga acctgggaag gagagaggag tacgacgtgc tggacaagcg acgcggacgc 1260 aacgagctga acctgggaag gagagaggag tacgacgtgo tggacaagcg acgcggacgc 1260

gacccggaga tgggggggaa accacggcgg aaaaaccctc aggaaggact gtacaacgaa 1320 gacccggaga tgggggggaa accacggcgg aaaaaccctc aggaaggact gtacaacgaa 1320

ctccagaaag acaagatggc ggaagcctac tcagaaatcg ggatgaaggg agagcggagg 1380 ctccagaaag acaagatggo ggaagcctac tcagaaatcg ggatgaaggg agagcggagg 1380

aggggaaagg gtcacgacgg gctgtaccag ggactgagca ccgccactaa ggatacctac 1440 aggggaaagg gtcacgacgg gctgtaccag ggactgagca ccgccactaa ggatacctac 1440

gatgccttgc atatgcaagc actcccaccc cgg 1473 gatgccttgo atatgcaagc actcccaccc cgg 1473

<210> 34 <210> 34 <211> 491 <211> 491 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 34 <400> 34 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Asp Ser Val Ser Ser Asn Ser Ala Thr Trp Asn Trp Ile Arg Gln Ser Asp Ser Val Ser Ser Asn Ser Ala Thr Trp Asn Trp Ile Arg Gln Ser 50 55 60 50 55 60

Page 29 Page 29

SequenceListing (3).txt SequenceListing (3) . txt

Pro Ser Gly Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Pro Ser Gly Gly Leu Glu Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys 65 70 75 80 70 75 80

Trp Tyr Asp Asp Tyr Ala Val Ser Val Arg Ser Arg Ile Thr Met Asn Trp Tyr Asp Asp Tyr Ala Val Ser Val Arg Ser Arg Ile Thr Met Asn 85 90 95 85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Val Ala Gly Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Val Ala Gly 115 120 125 115 120 125

Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 130 135 140 130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 145 150 155 160 145 150 155 160

Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 165 170 175 165 170 175

Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 180 185 190 180 185 190

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 195 200 205 195 200 205

Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 210 215 220 210 215 220

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 225 230 235 240 225 230 235 240

Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe 245 250 255 245 250 255

Page 30 Page 30

SequenceListing (3).txt SequenceListing (3) . txt

Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Pro Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Pro 260 265 270 260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 275 280 285 275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 290 295 300 290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 305 310 315 320 305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 325 330 335 325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 340 345 350 340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 355 360 365 355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser 370 375 380 370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 385 390 395 400 385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 405 410 415 405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn 420 425 430 420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 435 440 445 435 440 445

Page 31 Page 31

SequenceListing (3).txt SequenceListing (3) . txt

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 450 455 460 450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 465 470 475 480 465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 485 490

<210> 35 <210> 35 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 35 <400> 35 Gln Ser Ile Ser Ser Tyr Gln Ser Ile Ser Ser Tyr 1 5 1 5

<210> 36 <210> 36 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 36 <400> 36 Ala Ala Ser Ala Ala Ser 1 1

<210> 37 <210> 37 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic Page 32 Page 32

SequenceListing (3).txt SequenceListing (3) txt peptide peptide

<400> 37 <400> 37 Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Gln Gln Ser Tyr Ser Thr Pro Tyr Thr 1 5 1 5

<210> 38 <210> 38 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 38 <400> 38 Gly Asp Ser Val Ser Ser Asn Ser Ala Thr Gly Asp Ser Val Ser Ser Asn Ser Ala Thr 1 5 10 1 5 10

<210> 39 <210> 39 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 39 <400> 39 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asp Thr Tyr Tyr Arg Ser Lys Trp Tyr Asp 1 5 1 5

<210> 40 <210> 40 <211> 11 <211> 11 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 40 <400> 40 Ala Arg Glu Gly Val Ala Gly Asp Phe Asp Tyr Ala Arg Glu Gly Val Ala Gly Asp Phe Asp Tyr 1 5 10 1 5 10

Page 33 Page 33

SequenceListing (3).txt SequenceListing (3) . txt

<210> 41 <210> 41 <211> 726 <211> 726 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 41 <400> 41 caagttcagt tgcagcagag tggccctggg cttgttaaac catcacagac gctctcactg 60 caagttcagt tgcagcagag tggccctggg cttgttaaac catcacagac gctctcactg 60

acctgtgcca tctctggaga cagtgtaagt tctaactcag ccgcgtggaa ttggattaga 120 acctgtgcca tctctggaga cagtgtaagt tctaactcag ccgcgtggaa ttggattaga 120

caatcaccaa gccggggact tgaatggctt ggtcggacgt actatagatc taagtggtat 180 caatcaccaa gccggggact tgaatggctt ggtcggacgt actatagatc taagtggtat 180

aatgactacg cagtgtcagt gaaatcacgg ataaccataa accctgacac cagcaaaaac 240 aatgactacg cagtgtcagt gaaatcacgg ataaccataa accctgacac cagcaaaaac 240

caattttctc ttcagcttaa ttccgtcacg ccagaagata cggccgttta ctactgtgcg 300 caattttctc ttcagcttaa ttccgtcacg ccagaagata cggccgttta ctactgtgcg 300

agggaaggtg atgacgcatt ggacatctgg ggtcagggga ccatggtgac tgtctcttcc 360 agggaaggtg atgacgcatt ggacatctgg ggtcagggga ccatggtgac tgtctcttcc 360

ggcggggggg gtagtggagg gggtggctca ggtggtggcg ggtcagatat acaaatgaca 420 ggcggggggg gtagtggagg gggtggctca ggtggtggcg ggtcagatat acaaatgaca 420

cagagcccta gtagtctgag tgcttcagtg ggcgaccgcg taactataac ctgtagagca 480 cagagcccta gtagtctgag tgcttcagtg ggcgaccgcg taactataac ctgtagagca 480

tcccaaagca tttcccactt ccttaattgg taccagcaga agccgggcac agcgcccaaa 540 tcccaaagca tttcccactt ccttaattgg taccagcaga agccgggcac agcgcccaaa 540

ctcctgatca ccactgcgag cggacttggt tcaggtgttc ctagccggtt tagtgggtca 600 ctcctgatca ccactgcgag cggacttggt tcaggtgttc ctagccggtt tagtgggtca 600

ggtagcggta cagatttcac tctcacgata aactcccttc agcctgagga cctggcgaca 660 ggtagcggta cagatttcac tctcacgata aactcccttc agcctgagga cctggcgaca 660

tattactgtc aacaatccta taccacccca ctgacattcg gagggggcac aaaactggag 720 tattactgtc aacaatccta taccacccca ctgacattcg gagggggcac aaaactggag 720

atcaaa 726 atcaaa 726

<210> 42 <210> 42 <211> 243 <211> 243 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 42 <400> 42

Page 34 Page 34

SequenceListing (3).txt SequenceListing (3) txt Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Tyr Tyr Cys Ala Arg Glu Gly Asp Asp Ala Leu Asp Ile Trp Gly Gln Tyr Tyr Cys Ala Arg Glu Gly Asp Asp Ala Leu Asp Ile Trp Gly Gln 100 105 110 100 105 110

Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 115 120 125

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 130 135 140

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 145 150 155 160

Ser Gln Ser Ile Ser His Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Ser Gln Ser Ile Ser His Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly 165 170 175 165 170 175

Thr Ala Pro Lys Leu Leu Ile Thr Thr Ala Ser Gly Leu Gly Ser Gly Thr Ala Pro Lys Leu Leu Ile Thr Thr Ala Ser Gly Leu Gly Ser Gly 180 185 190 180 185 190

Page 35 Page 35

SequenceListing (3).txt Val Pro Ser Arg Phe Ser Gly Ser SequenceListing (3) . txt Gly Ser Gly Thr Asp Phe Thr Leu Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 195 200 205

Thr 210 Ile Asn Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Thr Ile Asn Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln 210 215 220 215 220

Gln 225 Ser Tyr Thr Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Gln Ser Tyr Thr Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu 225 230 235 240 230 235 240

Ile Lys Arg Ile Lys Arg

<210> 43 <210> 43 <211> 1470 <211> 1470 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 43 <400> 43 atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60 60 atcccacaag ttcagttgca gcagagtggo cctgggcttg ttaaaccatc acagacgctc atcccacaag ttcagttgca gcagagtggc cctgggcttg ttaaaccatc acagacgctc 120 120 tcactgacct gtgccatctc tggagacagt gtaagttcta actcagccgc gtggaattgg tcactgacct gtgccatctc tggagacagt gtaagttcta actcagccgc gtggaattgg 180 180 attagacaat caccaagccg gggacttgaa tggcttggtc ggacgtacta tagatctaag attagacaat caccaagccg gggacttgaa tggcttggtc ggacgtacta tagatctaag 240 240 tggtataatg actacgcagt gtcagtgaaa tcacggataa ccataaaccc tgacaccagc tggtataatg actacgcagt gtcagtgaaa tcacggataa ccataaaccc tgacaccagc 300 300 aaaaaccaat tttctcttca gcttaattcc gtcacgccag aagatacggc cgtttactac aaaaaccaat tttctcttca gcttaattcc gtcacgccag aagatacggc cgtttactac 360 360 tgtgcgaggg aaggtgatga cgcattggac atctggggtc aggggaccat ggtgactgtc tgtgcgaggg aaggtgatga cgcattggac atctggggtc aggggaccat ggtgactgtc 420 420 tcttccggcg gggggggtag tggagggggt ggctcaggtg gtggcgggtc agatatacaa tcttccggcg gggggggtag tggagggggt ggctcaggtg gtggcgggtc agatatacaa 480 480 atgacacaga gccctagtag tctgagtgct tcagtgggcg accgcgtaac tataacctgt atgacacaga gccctagtag tctgagtgct tcagtgggcg accgcgtaac tataacctgt 540 540 agagcatccc aaagcatttc ccacttcctt aattggtacc agcagaagcc gggcacagcg agagcatccc aaagcatttc ccacttcctt aattggtacc agcagaagcc gggcacagcg 600 600 cccaaactco tgatcaccac tgcgagcgga cttggttcag gtgttcctag ccggtttagt cccaaactcc tgatcaccac tgcgagcgga cttggttcag gtgttcctag ccggtttagt 660 660

Page 36 Page 36

SequenceListing (3).txt SequenceListing (3) . txt gggtcaggta gcggtacaga tttcactctc acgataaact cccttcagcc tgaggacctg 720 gggtcaggta gcggtacaga tttcactctc acgataaact cccttcagcc tgaggacctg 720

gcgacatatt actgtcaaca atcctatacc accccactga cattcggagg gggcacaaaa 780 gcgacatatt actgtcaaca atcctatacc accccactga cattcggagg gggcacaaaa 780

ctggagatca aagcggccgc aactaccacc cctgcccctc ggccgccgac tccggcccca 840 ctggagatca aagcggccgc aactaccacc cctgcccctc ggccgccgac tccggcccca 840

accatcgcaa gccaacccct ctccttgcgc cccgaagctt gccgcccggc cgcgggtgga 900 accatcgcaa gccaacccct ctccttgcgc cccgaagctt gccgcccggc cgcgggtgga 900

gccgtgcata cccgggggct ggactttgcc tgcgatatct acatttgggc cccgctggcc 960 gccgtgcata cccgggggct ggactttgcc tgcgatatct acatttgggc cccgctggcc 960

ggcacttgcg gcgtgctcct gctgtcgctg gtcatcaccc tttactgcaa gaggggccgg 1020 ggcacttgcg gcgtgctcct gctgtcgctg gtcatcaccc tttactgcaa gaggggccgg 1020

aagaagctgc tttacatctt caagcagccg ttcatgcggc ccgtgcagac gactcaggaa 1080 aagaagctgc tttacatctt caagcagccg ttcatgcggc ccgtgcagac gactcaggaa 1080

gaggacggat gctcgtgcag attccctgag gaggaagagg ggggatgcga actgcgcgtc 1140 gaggacggat gctcgtgcag attccctgag gaggaagagg ggggatgcga actgcgcgtc 1140

aagttctcac ggtccgccga cgcccccgca tatcaacagg gccagaatca gctctacaac 1200 aagttctcac ggtccgccga cgcccccgca tatcaacagg gccagaatca gctctacaac 1200

gagctgaacc tgggaaggag agaggagtac gacgtgctgg acaagcgacg cggacgcgac 1260 gagctgaacc tgggaaggag agaggagtac gacgtgctgg acaagcgacg cggacgcgac 1260

ccggagatgg gggggaaacc acggcggaaa aaccctcagg aaggactgta caacgaactc 1320 ccggagatgg gggggaaacc acggcggaaa aaccctcagg aaggactgta caacgaacto 1320

cagaaagaca agatggcgga agcctactca gaaatcggga tgaagggaga gcggaggagg 1380 cagaaagaca agatggcgga agcctactca gaaatcggga tgaagggaga gcggaggagg 1380

ggaaagggtc acgacgggct gtaccaggga ctgagcaccg ccactaagga tacctacgat 1440 ggaaagggtc acgacgggct gtaccaggga ctgagcaccg ccactaagga tacctacgat 1440

gccttgcata tgcaagcact cccaccccgg 1470 gccttgcata tgcaagcact cccaccccgg 1470

<210> 44 <210> 44 <211> 490 <211> 490 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 44 <400> 44 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly

Page 37 Page 37

SequenceListing (3).txt SequenceListing (3) txt 35 40 45 35 40 45

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Asp Asp Ala Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Asp Asp Ala 115 120 125 115 120 125

Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly 130 135 140 130 135 140

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln 145 150 155 160 145 150 155 160

Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 165 170 175 165 170 175

Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser His Phe Leu Asn Trp Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser His Phe Leu Asn Trp 180 185 190 180 185 190

Tyr Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Leu Ile Thr Thr Ala Tyr Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Leu Ile Thr Thr Ala 195 200 205 195 200 205

Ser Gly Leu Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Ser Gly Leu Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 210 215 220 210 215 220

Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu Asp Leu Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu Asp Leu Page 38 Page 38

SequenceListing (3).txt SequenceListing (3) . txt 225 230 235 240 225 230 235 240

Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Leu Thr Phe Gly Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Leu Thr Phe Gly 245 250 255 245 250 255

Gly Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Pro Ala Gly Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Pro Ala 260 265 270 260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 305 310 315 320 305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 325 330 335 325 330 335

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 340 345 350 340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 355 360 365 355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 370 375 380 370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 385 390 395 400 385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 405 410 415 405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Page 39 Page 39

SequenceListing (3).txt SequenceListing (3) . txt 420 425 430 420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 435 440 445 435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 450 455 460 450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 465 470 475 480 465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 485 490

<210> 45 <210> 45 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 45 <400> 45 Gln Ser Ile Ser His Phe Gln Ser Ile Ser His Phe 1 5 1 5

<210> 46 <210> 46 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 46 <400> 46 Thr Ala Ser Thr Ala Ser 1 1

<210> 47 <210> 47

Page 40 Page 40

<400> 47 <400> 47 Gln Gln Ser Tyr Thr Thr Pro Leu Thr Gln Gln Ser Tyr Thr Thr Pro Leu Thr 1 5 1 5

<210> 48 <210> 48 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 48 <400> 48 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 49 <210> 49 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 49 <400> 49 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 50 <210> 50 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic Page 41 Page 41

SequenceListing (3).txt SequenceListing (3) . txt peptide peptide

<400> 50 <400> 50 Ala Arg Glu Gly Asp Asp Ala Leu Asp Ile Ala Arg Glu Gly Asp Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 51 <210> 51 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 51 <400> 51 cagatacagt tgcagcagtc aggtccagga ctagtgaagc cctcgcagac cctctcactc 60 cagatacagt tgcagcagto aggtccagga ctagtgaago cctcgcagac cctctcactc 60

acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120 acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180 cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240 aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240

cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc 300 cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc 300

caagaggtac aacctgatga tgctttagat atctggggcc aagggacaat ggtcaccgtc 360 caagaggtac aacctgatga tgctttagat atctggggcc aagggacaat ggtcaccgtc 360

tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgacatccag 420 tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgacatccag 420

atgacccagt ctccatcttc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480 atgacccagt ctccatcttc cgtgtctgca tctgtaggag acaaagtcad catcacttgt 480

cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540 cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540

cctcagctcc tgatctctgg tgcatccact ttgcaaggtg aagtcccatc aaggttcagc 600 cctcagctcc tgatctctgg tgcatccact ttgcaaggtg aagtcccatc aaggttcagc 600

ggcagtggat ctgggacaga ttttactctc accatcagca gcctgcagcc tgaagatttt 660 ggcagtggat ctgggacaga ttttactctc accatcagca gcctgcagcc tgaagatttt 660

gccacttatt attgtcaaca ggctaaaaat ttcccttaca cttttggcca ggggaccaag 720 gccacttatt attgtcaaca ggctaaaaat ttcccttaca cttttggcca ggggaccaag 720

ctggaaatca aa 732 ctggaaatca aa 732

<210> 52 <210> 52 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence Page 42 Page 42

SequenceListing (3).txt SequenceListing (3) . txt

<400> 52 <400> 52 Gln Ile Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Ile Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp Asp Ala Leu Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp Asp Ala Leu Asp Ile Trp 100 105 110 100 105 110

Page 43 Page 43

SequenceListing (3).txt SequenceListing (3) . txt

Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser Gly Ala Ser Thr Leu Gln Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser Gly Ala Ser Thr Leu Gln 180 185 190 180 185 190

Cys 225 Gln Gln Ala Lys Asn Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Cys Gln Gln Ala Lys Asn Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 230 235 240

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 53 <210> 53 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 53 <400> 53 atgttgttgc ttgtcacaag ccttcttctc tgtgagcttc cgcacccggc tttcctgctg atgttgttgc ttgtcacaag ccttcttctc tgtgagcttc cgcacccggc tttcctgctg 60 60 atcccgcaga tacagcttca gcagtccggc cccggtctgg taaagccgtc ccaaacgctt atcccgcaga tacagcttca gcagtccggc cccggtctgg taaagccgtc ccaaacgctt 120 120 tcactcacat gcgcgatctc tggtgattct gtgtcatcca acagcgcago atggaattgg tcactcacat gcgcgatctc tggtgattct gtgtcatcca acagcgcagc atggaattgg 180 180 atccgccaat cacccagtag aggcttggag tggttgggcc ggacttatta tcgaagtaag atccgccaat cacccagtag aggcttggag tggttgggcc ggacttatta tcgaagtaag 240 240 tggtacaatg attatgcagt ctcagttaaa tccaggatca ctattaaccc agatacaagt tggtacaatg attatgcagt ctcagttaaa tccaggatca ctattaaccc agatacaagt 300 300

aaaaaccagt tctcattgca acttaattco gtaactccgg aggacactgc agtatattad aaaaaccagt tctcattgca acttaattcc gtaactccgg aggacactgc agtatattac 360 360 tgcgctcagg aggtgcagcc tgatgatgct ctggacattt ggggacaagg cacgatggtc tgcgctcagg aggtgcagcc tgatgatgct ctggacattt ggggacaagg cacgatggtc 420 420 acggttagtt ccgggggggg aggttctggc ggaggtggta gtgggggggg cggcagtgac acggttagtt ccgggggggg aggttctggc ggaggtggta gtgggggggg cggcagtgac 480 480

Page 44 Page 44

SequenceListing (3).txt SequenceListing (3) . txt atccagatga cacagagtcc cagcagcgtg tctgcgtcag tcggggataa ggtaacaatt 540 atccagatga cacagagtcc cagcagcgtg tctgcgtcag tcggggataa ggtaacaatt 540

acgtgtagag cgagccagga cgtttccggg tggctggcgt ggtaccaaca aaaacccggt 600 acgtgtagag cgagccagga cgtttccggg tggctggcgt ggtaccaaca aaaacccggt 600

ctcgctccgc agttgctcat ctctggagcg tccacccttc agggagaggt gcctagcaga 660 ctcgctccgc agttgctcat ctctggagcg tccacccttc agggagaggt gcctagcaga 660

ttttctgggt ctggatccgg cacggatttt acacttacga tttcctctct tcaacccgaa 720 ttttctgggt ctggatccgg cacggatttt acacttacga tttcctctct tcaacccgaa 720

gattttgcta cttactattg ccagcaggcc aaaaacttcc cgtacacgtt tggacagggc 780 gattttgcta cttactattg ccagcaggcc aaaaacttcc cgtacacgtt tggacagggo 780

acaaagttgg aaattaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840 acaaagttgg aaattaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140

tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 tacaacgago tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260

gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 gaactccaga aagacaagat ggcggaagco tactcagaaa tcgggatgaa gggagagcgg 1380

<210> 54 <210> 54 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 54 <400> 54 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 45 Page 45

SequenceListing (3).txt SequenceListing (3) . txt

Ala Phe Leu Leu Ile Pro Gln Ile Gln Leu Gln Gln Ser Gly Pro Gly Ala Phe Leu Leu Ile Pro Gln Ile Gln Leu Gln Gln Ser Gly Pro Gly 20 25 30 20 25 30

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp 115 120 125 115 120 125

Asp Ala Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Asp Ala Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 130 135 140 130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 145 150 155 160 145 150 155 160

Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser Ala Trp Tyr Gln Gln Lys Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser 195 200 205 195 200 205

Page 46 Page 46

SequenceListing (3).txt SequenceListing (3) . txt

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro 340 345 350 340 345 350

Page 47 Page 47

SequenceListing (3).txt SequenceListing (3) . txt

<210> 55 <210> 55 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 55 <400> 55 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 56 <210> 56 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 48 Page 48

SequenceListing (3).txt SequenceListing (3) txt <400> 56 <400> 56 Gly Ala Ser Gly Ala Ser 1 1

<210> 57 <210> 57 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 57 <400> 57 Gln Gln Ala Lys Asn Phe Pro Tyr Thr Gln Gln Ala Lys Asn Phe Pro Tyr Thr 1 5 1 5

<210> 58 <210> 58 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 58 <400> 58 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 59 <210> 59 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 59 <400> 59 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 60 <210> 60

Page 49 Page 49

SequenceListing (3).txt SequenceListing (3) txt <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 60 <400> 60 Ala Gln Glu Val Gln Pro Asp Asp Ala Leu Asp Ile Ala Gln Glu Val Gln Pro Asp Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 61 <210> 61 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 61 <400> 61 caagtacagt tgcagcagtc aggacctggc cttgtgaaac catcccaaac tctcagcctc 60 caagtacagt tgcagcagtc aggacctggc cttgtgaaac catcccaaac tctcagcctc 60

acgtgtgcta tttctggtga ctcagtaagt agcaatagcg ctgcttggaa ctggatcaga 120 acgtgtgcta tttctggtga ctcagtaagt agcaatagcg ctgcttggaa ctggatcaga 120

caatctccct ccaggggtct cgaatggctg gggcgaacct attaccgatc taaatggtat 180 caatctccct ccaggggtct cgaatggctg gggcgaacct attaccgatc taaatggtat 180

aacgattatg cagtatccgt gaaatccagg attacaatca acccagatac gttcaagaat 240 aacgattatg cagtatccgt gaaatccagg attacaatca acccagatad gttcaagaat 240

caattctctc ttcagctcaa ctccgtaact ccagaggaca ctgcggtata ttattgcgcc 300 caattctctc ttcagctcaa ctccgtaact ccagaggaca ctgcggtata ttattgcgcc 300

caagaagtcg agccacacga tgccctcgat atctggggtc aaggtaccat ggttacagtt 360 caagaagtcg agccacacga tgccctcgat atctggggto aaggtaccat ggttacagtt 360

agtagtgggg gtgggggaag cgggggcggt gggtccggtg gegggggttc agacatcaag agtagtgggg gtgggggaag cgggggcggt gggtccggtg gcgggggttc agacatcaag 420 420

atgacccaat ccccaagctc tgtttcagca tccgtgggcg ataaggtaac cattacatgc atgacccaat ccccaagctc tgtttcagca tccgtgggcg ataaggtaac cattacatgc 480 480

agagcgagtc aggacgtttc agggtggctg gcttggtacc agcaaaaacc gggactcgca 540 agagcgagtc aggacgtttc agggtggctg gcttggtacc agcaaaaacc gggactcgca 540

ccgcagctgt tgattttcgg cgccagtacg cttcagggcg aagtaccgtc caggttcagt 600 ccgcagctgt tgattttcgg cgccagtacg cttcagggcg aagtaccgtc caggttcagt 600

gggtcaggtt ctggcaccga ttttacgctc acgatatcca gtctccaacc ggaggatttt 660 gggtcaggtt ctggcaccga ttttacgctc acgatatcca gtctccaacc ggaggatttt 660

gctacttatt actgccagca ggctaagtat tttccataca catttggcca ggggacaaag gctacttatt actgccagca ggctaagtat tttccataca catttggcca ggggacaaag 720 720

ttggagatca aa 732 ttggagatca aa 732

Page 50 Page 50

SequenceListing (3).txt SequenceListing (3) txt

<210> 62 <210> 62 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 62 <400> 62 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Phe Lys Asn Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Phe Lys Asn 65 70 75 80 70 75 80

Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Trp 100 105 110 100 105 110

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Met Thr Gln Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Lys Met Thr Gln Ser 130 135 140 130 135 140

Page 51 Page 51

SequenceListing (3).txt SequenceListing (3) . txt Pro Ser Ser Val Ser Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys Pro Ser Ser Val Ser Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys 145 150 155 160 145 150 155 160

Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 225 230 235 240

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 63 <210> 63 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 63 <400> 63 atgctgcttt tggtaacttc cctccttttg tgcgagctgc cccatccagc gttcctcctc 60 atgctgcttt tggtaacttc cctccttttg tgcgagctgc cccatccago gttcctcctc 60

atccctcaag tacagttgca gcagtcagga cctggccttg tgaaaccatc ccaaactctc 120 atccctcaag tacagttgca gcagtcagga cctggccttg tgaaaccatc ccaaactctc 120

agcctcacgt gtgctatttc tggtgactca gtaagtagca atagcgctgc ttggaactgg 180 agcctcacgt gtgctatttc tggtgactca gtaagtagca atagcgctgc ttggaactgg 180

atcagacaat ctccctccag gggtctcgaa tggctggggc gaacctatta ccgatctaaa 240 atcagacaat ctccctccag gggtctcgaa tggctggggc gaacctatta ccgatctaaa 240

tggtataacg attatgcagt atccgtgaaa tccaggatta caatcaaccc agatacgttc 300 tggtataacg attatgcagt atccgtgaaa tccaggatta caatcaaccc agatacgttc 300

Page 52 Page 52

SequenceListing (3).txt SequenceListing (3) . txt aagaatcaat tctctcttca gctcaactcc gtaactccag aggacactgo ggtatattat aagaatcaat tctctcttca gctcaactcc gtaactccag aggacactgc ggtatattat 360 360 tgcgcccaag aagtcgagcc acacgatgcc ctcgatatct ggggtcaagg taccatggtt tgcgcccaag aagtcgagcc acacgatgcc ctcgatatct ggggtcaagg taccatggtt 420 420 acagttagta gtgggggtgg gggaagcggg ggcggtgggt ccggtggcgg gggttcagac acagttagta gtgggggtgg gggaagcggg ggcggtgggt ccggtggcgg gggttcagac 480 480 atcaagatga cccaatcccc aagctctgtt tcagcatccg tgggcgataa ggtaaccatt atcaagatga cccaatcccc aagctctgtt tcagcatccg tgggcgataa ggtaaccatt 540 540 acatgcagag cgagtcagga cgtttcaggg tggctggctt ggtaccagca aaaaccggga acatgcagag cgagtcagga cgtttcaggg tggctggctt ggtaccagca aaaaccggga 600 600 ctcgcaccgc agctgttgat tttcggcgcc agtacgcttc agggcgaagt accgtccagg ctcgcaccgc agctgttgat tttcggcgcc agtacgcttc agggcgaagt accgtccagg 660 660 ttcagtgggt caggttctgg caccgatttt acgctcacga tatccagtct ccaaccggag ttcagtgggt caggttctgg caccgatttt acgctcacga tatccagtct ccaaccggag 720 720 gattttgcta cttattactg ccagcaggct aagtattttc catacacatt tggccagggg gattttgcta cttattactg ccagcaggct aagtattttc catacacatt tggccagggg 780 780 acaaagttgg agatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg acaaagttgg agatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840 840 gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 900 ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960 960 ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020 1020 ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 1080 caggaagagg acggatgctc gtgcagattc cctgaggagg aagaggggeg atgcgaactg caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 1140 cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200 1200 tacaacgage tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 1260 cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320 1320 gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 1380 aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440 1440

tacgatgcct tgcatatgca agcactccca ccccgg tacgatgcct tgcatatgca agcactccca ccccgg 1476 1476

<210> 64 <210> 64 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> Description of Artificial Sequence: Synthetic <223> <223> Description of Artificial Sequence: Synthetic Page 53 Page 53

SequenceListing (3).txt SequenceListing (3) txt polypeptide polypeptide

<400> 64 <400> 64 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Pro Asp Thr Phe Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Asp Thr Phe Lys Asn Gln Phe Ser Leu Gln Leu Asn Ser Val Thr 100 105 110 100 105 110

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Glu Pro His 115 120 125 115 120 125

Ile Lys Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp 165 170 175 165 170 175

Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Page 54 Page 54

SequenceListing (3).txt SequenceListing (3) txt 180 185 190 180 185 190

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 245 250 255 245 250 255

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Page 55 Page 55

SequenceListing (3).txt SequenceListing (3) . txt 370 375 380 370 375 380

<210> 65 <210> 65 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 65 <400> 65 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 66 <210> 66 <211> 3 <211> 3 <212> PRT <212> PRT

Page 56 Page 56

SequenceListing (3).txt SequenceListing (3) . txt <213> Artificial Sequence <213> Artificial Sequence

<400> 66 <400> 66 Gly Ala Ser Gly Ala Ser 1 1

<210> 67 <210> 67 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 67 <400> 67 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 68 <210> 68 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 68 <400> 68 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 69 <210> 69 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 57 Page 57

SequenceListing (3).txt SequenceListing (3) txt <400> 69 <400> 69 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 70 <210> 70 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 70 <400> 70 Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 71 <210> 71 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 71 <400> 71 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacago tgcagcagtc aggtccagga ctggtgaagc cctcgcagad cctctcactc 60

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180 cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggto caagtggtat 180

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240 aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacao atccaagaad 240

caagaggtag aacctcatga tgctcttgat atctggggcc aagggacaat ggtcaccgtc 360 caagaggtag aacctcatga tgctcttgat atctggggcc aagggacaat ggtcaccgtc 360

tcttcaggag gtggcgggtc tggcggaggc ggtagcggtg gtggcggatc cgacatccag 420 tcttcaggag gtggcgggtc tggcggaggo ggtagcggtg gtggcggato cgacatccag 420

atgacgcagt ctccatcatc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480 atgacgcagt ctccatcato cgtgtctgca tctgtaggag acaaagtcad catcacttgt 480

cgggcgagtc aggatgttag cggctggtta gcctggtatc aacagaaacc agggctagcc 540 cgggcgagtc aggatgttag cggctggtta gcctggtatc aacagaaaco agggctagcc 540

cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccatc aaggttcagc 600 cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccato aaggttcagc 600

Page 58 Page 58

SequenceListing (3).txt SequenceListing (3) txt

gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggcca ggggaccaag 720 gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggcca ggggaccaag 720

ctggagatca aa 732 ctggagatca aa 732

<210> 72 <210> 72 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 72 <400> 72 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 59 Page 59

SequenceListing (3).txt SequenceListing (3) txt

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 73 <210> 73 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 73 <400> 73 atgctgctcc tcgtaacctc tcttcttctt tgtgagttgc cacatccagc atttcttctg 60 atgctgctcc tcgtaacctc tcttcttctt tgtgagttgc cacatccago atttcttctg 60

atacctcaag ttcaactcca gcagagtggt ccaggtttgg taaaacccag ccagactctc 120 atacctcaag ttcaactcca gcagagtggt ccaggtttgg taaaacccag ccagactctc 120

Page 60 Page 60

SequenceListing (3).txt SequenceListing (3) txt tcattgacgt gtgccatatc aggtgattca gtttcctcta atagcgcggc atggaattgg 180 tcattgacgt gtgccatato aggtgattca gtttcctcta atagcgcggc atggaattgg 180

atcaggcaaa gccctagtcg cgggctggag tggctcggcc ggacatacta ccgctcaaag 240 atcaggcaaa gccctagtcg cgggctggag tggctcggcc ggacatacta ccgctcaaag 240

tggtacaacg actacgccgt cagcgtaaaa tctcggatta ccattaaccc ggatacttcc 300 tggtacaacg actacgccgt cagcgtaaaa tctcggatta ccattaaccc ggatacttcc 300

aaaaaccaat tctccctgca gcttaacagt gtcacgccgg aagatacggc cgtttattac 360 aaaaaccaat tctccctgca gcttaacagt gtcacgccgg aagatacggc cgtttattac 360

tgcgcacaag aggtggaacc gcacgacgcc ctcgatatct ggggccaagg cactatggtg 420 tgcgcacaag aggtggaacc gcacgacgcc ctcgatatct ggggccaagg cactatggtg 420

accgtcagta gcggaggggg gggttccgga ggaggcggct ctggtggcgg aggatctgat 480 accgtcagta gcggaggggg gggttccgga ggaggcggct ctggtggcgg aggatctgat 480

atccaaatga cccaatcacc gtcttcagta tcagcttctg ttggtgacaa agttacgatt 540 atccaaatga cccaatcacc gtcttcagta tcagcttctg ttggtgacaa agttacgatt 540

acctgtcgag cgtcacagga cgtttctggt tggttggctt ggtatcagca aaaaccaggg 600 acctgtcgag cgtcacagga cgtttctggt tggttggctt ggtatcagca aaaaccaggg 600

cttgcgcctc agttgcttat ttttggggca tctactttgc agggagaggt gccctcccgg 660 cttgcgcctc agttgcttat ttttggggca tctactttgc agggagaggt gccctcccgg 660

ttctccggca gtgggagcgg caccgatttt acacttacca tctcttcctt gcaacccgaa 720 ttctccggca gtgggagcgg caccgatttt acacttacca tctcttcctt gcaacccgaa 720

gactttgcga cgtactattg ccagcaggca aagtattttc cctacacttt tggacaaggg 780 gactttgcga cgtactattg ccagcaggca aagtattttc cctacacttt tggacaaggg 780

actaaacttg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840 actaaacttg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

<210> 74 <210> 74

Page 61 Page 61

SequenceListing (3).txt SequenceListing (3) txt <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 74 <400> 74 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 62 Page 62

SequenceListing (3).txt SequenceListing (3) txt

Page 63 Page 63

SequenceListing (3).txt SequenceListing (3) . txt

<210> 75 <210> 75 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 75 <400> 75 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp Page 64 Page 64

SequenceListing (3).txt SequenceListing (3) txt 1 5 1 5

<210> 76 <210> 76 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 76 <400> 76 Gly Ala Ser Gly Ala Ser 1 1

<210> 77 <210> 77 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 77 <400> 77 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 78 <210> 78 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 78 <400> 78 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 79 <210> 79 <211> 9 <211> 9 <212> PRT <212> PRT

Page 65 Page 65

<400> 79 <400> 79 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 80 <210> 80 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 80 <400> 80 Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 81 <210> 81 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 81 <400> 81 caggtacago tgcagcagto aggtccagga ctggtgaagc cctcgcagac cctctcactc caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 60

acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120 120

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggto caagtggtat cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180 180

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacao attcaagaad aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac attcaagaac 240 240

cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc 300 300

caagaggtag aacctcatga tgctcttgat atctggggcd aagggacaat ggtcaccgtc caagaggtag aacctcatga tgctcttgat atctggggcc aagggacaat ggtcaccgtc 360 360

tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggato cgacatcaag tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgacatcaag 420 420

Page 66 Page 66

SequenceListing (3).txt SequenceListing (3) . txt

atgacccagt ctccatcttc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480 atgacccagt ctccatcttc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480

cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccatc aaggttcagc 600 cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccatc aaggttcago 600

ctggaaatca aa 732 ctggaaatca aa 732

<210> 82 <210> 82 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 82 <400> 82 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 67 Page 67

SequenceListing (3).txt SequenceListing (3) . txt Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Trp 100 105 110 100 105 110

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 83 <210> 83 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 68 Page 68

SequenceListing (3).txt 7x7 (E)

<400> 83 E8 <00 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60 7770779878 09

attccccaag tccagctcca acaatccgga cccggacttg ttaagccgtc tcagacgttg 120 OZI

tcactcacat gcgccatcag tggcgatagc gtgtccagca acagtgccgc atggaattgg 180 08T

atacgacaga gcccttcccg aggattggaa tggctgggac gaacgtacta taggtccaag 240

tggtataacg actacgcggt gtcagttaaa tctcggatta ctataaatcc cgacactttt 300 00E

aagaatcagt tttccctgca actcaattca gtcacaccgg aagatacggc agtgtactat 360 09E

tgcgctcaag aagttgagcc acatgatgcg ctggatattt ggggtcaggg gactatggtg 420

acggtaagca gtgggggcgg gggcagtggc ggaggtggca gcgggggcgg tggaagcgac 480 08/

attaagatga ctcagtctcc gtcttcagtt tccgcctccg taggggacaa ggttacaatt 540

acttgtcgcg catctcagga tgtctcaggt tggctggctt ggtatcaaca gaagcctggc 600 009

ctcgcccctc agcttctcat attcggggct agtaccctgc aaggagaagt cccgagcagg 660 099 cheese ttttccggtt cagggtccgg gacagacttt accttgacca tcagctccct gcaaccggag 720 OZL

gacttcgcga cctactattg tcaacaggcg aagtacttcc cctacacgtt cgggcaaggg 780 08L

actaagctcg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 006

ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960 096

ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020 0201

ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 080I

caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 DATE

cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200

tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 The cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320 9999991e8e OZET

gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 08EI

Page 69 69 aged

SequenceListing (3).txt SequenceListing (3) txt aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440 aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440

<210> 84 <210> 84 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 84 <400> 84 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Asp Ala Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Asp Ala Leu Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Page 70 Page 70

SequenceListing (3).txt SequenceListing (3) . txt 130 135 140 130 135 140

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Page 71 Page 71

SequenceListing (3).txt SequenceListing (3) . txt 325 330 335 325 330 335

<210> 85 <210> 85 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 72 Page 72

SequenceListing (3).txt SequenceListing (3) txt <220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic peptide peptide

<400> 85 <400> 85 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 86 <210> 86 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 86 <400> 86 Gly Ala Ser Gly Ala Ser 1 1

<210> 87 <210> 87 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 87 <400> 87 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 88 <210> 88 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 88 <400> 88 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Page 73 Page 73

SequenceListing (3).txt SequenceListing (3) . txt 1 5 10 1 5 10

<210> 89 <210> 89 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 89 <400> 89 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 90 <210> 90 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 90 <400> 90 Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 91 <210> 91 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 91 <400> 91 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacage tgcagcagtc aggtccagga ctggtgaagc cctcgcagad cctctcactc 60

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240 aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacao atccaagaac 240

Page 74 Page 74

SequenceListing (3).txt SequenceListing (3) . txt

cagttctccc tgcagctgaa ctctgtgact cccgaggata cggctgtgta ttactgtgcc 300 cagttctccc tgcagctgaa ctctgtgact cccgaggata cggctgtgta ttactgtgcc 300

caagaggtac aacctgatga tgcttttgat atctggggcc aagggacaat gatcaccgtc 360 caagaggtac aacctgatga tgcttttgat atctggggcc aagggacaat gatcaccgtc 360

cctcagctcc tgatctctgg tgcatccact ttgcaaggtg gagtcccatc aaggttcagc 600 cctcagctcc tgatctctgg tgcatccact ttgcaaggtg gagtcccatc aaggttcago 600

gccacttatt attgtcaaca ggctaaaaat ttcccttaca cttttggtca ggggaccaag 720 gccacttatt attgtcaaca ggctaaaaat ttcccttaca cttttggtca ggggaccaag 720

ctggaaatca aa 732 ctggaaatca aa 732

<210> 92 <210> 92 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 92 <400> 92 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 75 Page 75

SequenceListing (3).txt SequenceListing (3) txt

Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Gly Gln Gly Thr Met Ile Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gln Gly Thr Met Ile Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 115 120 125

Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 195 200 205

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 93 <210> 93 <211> 1476 <211> 1476

Page 76 Page 76

SequenceListing (3).txt <212> DNA <213> Artificial Sequence

<220> <223> Description of Artificial Sequence: Synthetic operating polynucleotide

<400> 93 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60

attccccaag tacaactcca gcaatcaggg cctggccttg tcaagccgag tcaaaccttg 120 00

agtttgacgt gtgccatcag cggtgactct gtcagttcaa actccgcagc ttggaactgg 180 as

attcggcagt ccccctccag gggcctcgaa tggcttggac ggacgtacta cagatcaaaa 240

tggtacaacg actacgcagt cagtgtaaaa tcaaggatta cgataaaccc tgatacgagt 300

aaaaaccagt tctctctcca actgaacagc gtcacaccgg aagatacagc cgtgtattac 360

tgtgctcagg aagtgcaacc tgacgacgca tttgacatct ggggtcaggg cacgatgatc 420

accgtgagta gtggaggagg aggcagtggg ggaggcggtt ctggcggggg tgggtctgat 480

atacagatga cacagagtcc ctcctcagtt tccgcctctg ttggagataa ggtgacaatt 540

acatgcaggg cgtcccaaga tgtttctgga tggctcgcat ggtaccaaca gaagccagga 600

ctcgcccctc agctcctcat tagcggcgct agcactctcc aagggggagt accgagcagg 660

ttctctgggt ccggaagtgg gacggacttt accctgacaa tatcctccct tcagccagaa 720

gacttcgcaa cctactattg ccaacaggcg aaaaatttcc cttacacgtt cggccaagga 780

actaaacttg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900

ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960

ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020

ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080

caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140

cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200

Page 77

SequenceListing (3).txt SequenceListing (3) txt tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 tacaacgage tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260

<210> 94 <210> 94 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 94 <400> 94 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 78 Page 78

SequenceListing (3).txt SequenceListing (3) txt

Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Ile Thr Val Ser Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Ile Thr Val Ser Ser 130 135 140 130 135 140

Gly Ala Ser Thr Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ala Ser Thr Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser 210 215 220 210 215 220

Page 79 Page 79

SequenceListing (3).txt SequenceListing (3) txt

Page 80 Page 80

SequenceListing (3).txt SequenceListing (3) txt

<210> 95 <210> 95 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 95 <400> 95 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 96 <210> 96 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 96 <400> 96 Gly Ala Ser Gly Ala Ser 1 1

<210> 97 <210> 97 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 97 <400> 97 Gln Gln Ala Lys Asn Phe Pro Tyr Thr Gln Gln Ala Lys Asn Phe Pro Tyr Thr 1 5 1 5

<210> 98 <210> 98 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 81 Page 81

<400> 98 <400> 98 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 99 <210> 99 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 99 <400> 99 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 100 <210> 100 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 100 <400> 100 Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 101 <210> 101 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 101 <400> 101 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacage tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60

Page 82 Page 82

SequenceListing (3).txt SequenceListing (3) . txt

caagaggtag aacctcagga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360 caagaggtag aacctcagga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360

tcttcaggag gtggcgggtc tggtggtggc ggtagcggtg gtggcggatc cgacatccag 420 tcttcaggag gtggcgggtc tggtggtggc ggtagcggtg gtggcggatc cgacatccag 420

cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540 cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagco 540

cctcagctcc tgatctttgg tgcatccact ctgcaaggtg aagtcccatc aaggttcagt 600 cctcagctcc tgatctttgg tgcatccact ctgcaaggtg aagtcccatc aaggttcagt 600

gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggccc ggggaccaag 720 gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggccc ggggaccaag 720

ctggaaatca aa 732 ctggaaatca aa 732

<210> 102 <210> 102 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 102 <400> 102 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 83 Page 83

SequenceListing (3).txt SequenceListing (3) txt Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 50 55 60

Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Pro Gly Thr Lys Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Pro Gly Thr Lys 225 230 235 240 225 230 235 240

Page 84 Page 84

SequenceListing (3).txt SequenceListing (3) txt Leu Glu Ile Lys Leu Glu Ile Lys

<210> 103 <210> 103 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 103 <400> 103 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60

attccccaag tgcagttgca acagtctgga ccaggcctcg taaaaccttc tcaaactttg 120 attccccaag tgcagttgca acagtctgga ccaggcctcg taaaaccttc tcaaactttg 120

tcactcactt gtgccatctc aggggacagt gtcagttcca acagtgcggc atggaattgg 180 tcactcactt gtgccatctc aggggacagt gtcagttcca acagtgcggc atggaattgg 180

attaggcaat ccccctctcg aggtctggaa tggcttgggc ggacttacta ccgaagtaag 240 attaggcaat cccccctctcg aggtctggaa tggcttgggc ggacttacta ccgaagtaag 240

tggtacaacg attatgcagt ttctgtaaaa tcacgaatca ctataaatcc ggacacttct 300 tggtacaacg attatgcagt ttctgtaaaa tcacgaatca ctataaatcc ggacacttct 300

aagaatcagt tctctttgca gcttaactct gttactcctg aagacacagc cgtatattac 360 aagaatcagt tctctttgca gcttaactct gttactcctg aagacacage cgtatattac 360

tgtgctcaag aggtagagcc gcaagatgcc ttcgacatct ggggccaagg gactatggtg 420 tgtgctcaag aggtagagcc gcaagatgcc ttcgacatct ggggccaagg gactatggtg 420

acagtaagct ccggaggtgg gggatcaggg ggaggtgggt ccggtggtgg tggctctgac 480 acagtaagct ccggaggtgg gggatcaggg ggaggtgggt ccggtggtgg tggctctgac 480

atacagatga cacagtcccc tagctctgtg tcagcaagtg tcggtgacaa ggttacgata 540 atacagatga cacagtcccc tagctctgtg tcagcaagtg tcggtgacaa ggttacgata 540

acgtgcaggg ccagtcaaga tgtgtcagga tggttggcgt ggtaccaaca gaaacccggc 600 acgtgcaggg ccagtcaaga tgtgtcagga tggttggcgt ggtaccaaca gaaacccggc 600

ttggcaccgc agcttttgat attcggcgcg tccacactcc aaggcgaagt gccttctcgg 660 ttggcaccgc agcttttgat attcggcgcg tccacactcc aaggcgaagt gccttctcgg 660

ttttctggaa gcggcagcgg gacggacttt actttgacaa tatcctccct ccaacccgag 720 ttttctggaa gcggcagcgg gacggacttt actttgacaa tatcctccct ccaacccgag 720

gatttcgcga cgtattattg ccagcaagca aaatacttcc catacacctt cgggcctggg 780 gatttcgcga cgtattattg ccagcaagca aaatacttcc catacacctt cgggcctggg 780

accaaactgg agatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840 accaaactgg agatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840

Page 85 Page 85

SequenceListing (3).txt SequenceListing (3) . txt ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080

<210> 104 <210> 104 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 104 <400> 104 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn Trp Tyr Asn Asp Tyr Ala Val Ser Val Lys Ser Arg Ile Thr Ile Asn

Page 86 Page 86

SequenceListing (3).txt SequenceListing (3) . txt 85 90 95 85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln 115 120 125 115 120 125

Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr 260 265 270 260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Page 87 Page 87

SequenceListing (3).txt SequenceListing (3) txt 275 280 285 275 280 285

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Page 88 Page 88

<210> 105 <210> 105 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 105 <400> 105 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 106 <210> 106 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 106 <400> 106 Gly Ala Ser Gly Ala Ser 1 1

<210> 107 <210> 107 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 107 <400> 107 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

Page 89 Page 89

SequenceListing (3).txt SequenceListing (3) txt

<210> 108 <210> 108 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 108 <400> 108 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 109 <210> 109 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 109 <400> 109 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 110 <210> 110 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 110 <400> 110 Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 111 <210> 111 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 90 Page 90

SequenceListing (3).txt SequenceListing (3) txt <220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic polynucleotide polynucleotide

<400> 111 <400> 111 caggtacagc tgcagcagtc aggtccagga ctggtgaagc actcgcagac cctctcactc 60 caggtacago tgcagcagtc aggtccagga ctggtgaagc actcgcagad cctctcactc 60

cagttctccc tgcagttgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc 300 cagttctccc tgcagttgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgcc 300

caagaggtag aacctcatga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360 caagaggtag aacctcatga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360

atgacccagt ctccatcttc cgtgtatgca tctgtaggag acaaagtcac catcacttgt 480 atgacccagt ctccatcttc cgtgtatgca tctgtaggag acaaagtcad catcacttgt 480

cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540 cgggcgagto aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540

cctcagctcc tgatctctgg tgcatccact ttgcaaggtg aagtcccatc aaggttcagc 600 cctcagctco tgatctctgg tgcatccact ttgcaaggtg aagtcccato aaggttcago 600

ggcagtggat ctgggacaga ttttactctc accatcagca gcctgcagcc tgaagatttt 660 ggcagtggat ctgggacaga ttttactctc accatcagca gcctgcagco tgaagatttt 660

ctggaaatca aa 732 ctggaaatca aa 732

<210> 112 <210> 112 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 112 <400> 112 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys His Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys His Ser Gln 1 5 10 15 1 5 10 15

Page 91 Page 91

SequenceListing (3).txt SequenceListing (3) txt

Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Glu Pro His Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Pro Ser Ser Val Tyr Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys Pro Ser Ser Val Tyr Ala Ser Val Gly Asp Lys Val Thr Ile Thr Cys 145 150 155 160 145 150 155 160

Page 92 Page 92

SequenceListing (3).txt SequenceListing (3) . txt

225 Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 230 235 240

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 113 <210> 113 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 113 <400> 113 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60 60 attccccagg tacagcttca acagagtggg ccgggactgg tgaaacacto ccaaacactt attccccagg tacagcttca acagagtggg ccgggactgg tgaaacactc ccaaacactt 120 120 tctctgacgt gcgctatatc aggtgactct gtttcatcta attctgctgc gtggaactgg tctctgacgt gcgctatatc aggtgactct gtttcatcta attctgctgc gtggaactgg 180 180 attcgacaat ctcccagtcg cgggttggaa tggctgggad gaacatatta tcggtctaag attcgacaat ctcccagtcg cgggttggaa tggctgggac gaacatatta tcggtctaag 240 240 tggtataacg attatgctgt atctgttaaa tctcgaatta cgattaatcc tgacacctcc tggtataacg attatgctgt atctgttaaa tctcgaatta cgattaatcc tgacacctcc 300 300

aagaaccagt tctccctcca gttgaactca gtcacaccgg aagacactgo ggtctactat aagaaccagt tctccctcca gttgaactca gtcacaccgg aagacactgc ggtctactat 360 360 tgcgctcaag aagtcgagcc acatgatgca ttcgacatct ggggccaggg aacgatggtc tgcgctcaag aagtcgagcc acatgatgca ttcgacatct ggggccaggg aacgatggtc 420 420 accgtcagca gtggcggcgg cggatctggg ggtggcggtt ctggcggtgg aggatcagac accgtcagca gtggcggcgg cggatctggg ggtggcggtt ctggcggtgg aggatcagac 480 480 atacaaatga cgcagagtcc ctcaagtgtg tacgcgagtg tgggggataa ggtaactatt atacaaatga cgcagagtcc ctcaagtgtg tacgcgagtg tgggggataa ggtaactatt 540 540 acgtgcagag cgtcacagga tgttagtgga tggcttgcct ggtatcagca gaagccaggo acgtgcagag cgtcacagga tgttagtgga tggcttgcct ggtatcagca gaagccaggc 600 600 cttgctccac agctccttat cagtggtgct tctacacttc agggcgaggt tccgagtaga cttgctccac agctccttat cagtggtgct tctacacttc agggcgaggt tccgagtaga 660 660 ttctctggtt ctggatctgg tactgacttc actcttacaa tttcttcttt gcaaccagaa ttctctggtt ctggatctgg tactgacttc actcttacaa tttcttcttt gcaaccagaa 720 720 gactttgcga cttattactg ccaacaggcc aaatacttcc cttatacatt tggccaaggt gactttgcga cttattactg ccaacaggcc aaatacttcc cttatacatt tggccaaggt 780 780 accaagttgg agataaaggc ggccgcaact accacccctg cccctcggcc gccgactccg accaagttgg agataaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840 840

Page 93 Page 93

SequenceListing (3).txt SequenceListing (3) . txt gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900

<210> 114 <210> 114 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 114 <400> 114 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Leu Val Lys His Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Leu Val Lys His Ser Gln Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly 35 40 45 35 40 45

Page 94 Page 94

SequenceListing (3).txt SequenceListing (3) . txt

Ile Gln Met Thr Gln Ser Pro Ser Ser Val Tyr Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Tyr Ala Ser Val Gly Asp 165 170 175 165 170 175

Page 95 Page 95

SequenceListing (3).txt SequenceListing (3) txt

Page 96 Page 96

SequenceListing (3).txt SequenceListing (3) . txt

<210> 115 <210> 115 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 115 <400> 115 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 116 <210> 116 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 116 <400> 116 Gly Ala Ser Gly Ala Ser 1 1

<210> 117 <210> 117 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic Page 97 Page 97

SequenceListing (3).txt SequenceListing (3) txt peptide peptide

<400> 117 <400> 117 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 118 <210> 118 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 118 <400> 118 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 119 <210> 119 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 119 <400> 119 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 120 <210> 120 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 120 <400> 120 Ala Gln Glu Val Glu Pro His Asp Ala Phe Asp Ile Ala Gln Glu Val Glu Pro His Asp Ala Phe Asp Ile 1 5 10 1 5 10

Page 98 Page 98

SequenceListing (3).txt SequenceListing (3) txt

<210> 121 <210> 121 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 121 <400> 121 caagtacaac ttcaacagtc tgggcctggg cttgtaaaac ctagccaaac tctgtccctc 60 caagtacaac ttcaacagtc tgggcctggg cttgtaaaac ctagccaaac tctgtccctc 60

acgtgcgcga tttcagggga cagtgtaagt tccaactcag ccgcatggaa ctggatcagg 120 acgtgcgcga tttcagggga cagtgtaagt tccaactcag ccgcatggaa ctggatcagg 120

cagtcacctt caagggggct cgaatggctt ggccgaacgt actacaggag taagtggtac 180 cagtcacctt caagggggct cgaatggctt ggccgaacgt actacaggag taagtggtac 180

aacgattatg cagtgtctgt gaaatcacgg attactatca atcccgacac gtccaagaac 240 aacgattatg cagtgtctgt gaaatcacgg attactatca atcccgacac gtccaagaac 240

cagttctctc tgcaactcaa ctcagtgaca ccagaggata cggccgttta ctattgtgca 300 cagttctctc tgcaactcaa ctcagtgaca ccagaggata cggccgttta ctattgtgca 300

caggaagtgc aacctgatga tgcctttgac atttggggtc agggcacgat ggttacggta 360 caggaagtgc aacctgatga tgcctttgac atttggggtc agggcacgat ggttacggta 360

agctctgggg gaggcggcag tggaggggga ggtagtgggg gagggggatc tgatatacag 420 agctctgggg gaggcggcag tggaggggga ggtagtgggg gagggggatc tgatatacag 420

atgacacaaa gcccgtcatc cgtcagtgct tcagttggtg ataaagtaac cattacgtgc 480 atgacacaaa gcccgtcatc cgtcagtgct tcagttggtg ataaagtaac cattacgtgc 480

cgcgcttccc aagacgttag cggatggttg gcttggtatc aacaaaaacc ggggttggct 540 cgcgcttccc aagacgttag cggatggttg gcttggtatc aacaaaaacc ggggttggct 540

ccgcaactcc tcatatccgg tgcgagtacg ctccaaggcg aagtccctag cagattttcc 600 ccgcaactcc tcatatccgg tgcgagtacg ctccaaggcg aagtccctag cagattttcc 600

gggagcggtt ccggtacaga tttcacgttg accattagct ctctccagcc cgaagatttt 660 gggagcggtt ccggtacaga tttcacgttg accattagct ctctccagcc cgaagatttt 660

gcaacctact attgccaaca ggccaaaaat tttccatata catttggtca aggcactaag 720 gcaacctact attgccaaca ggccaaaaat tttccatata catttggtca aggcactaag 720

ctcgaaatca aa 732 ctcgaaatca aa 732

<210> 122 <210> 122 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 122 <400> 122

Page 99 Page 99

Page 100 Page 100

SequenceListing (3).txt SequenceListing (3) . txt Gly Glu Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Gly Glu Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 195 200 205

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 123 <210> 123 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 123 <400> 123 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgo cttcctgctt atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60 60 attccccaag tacaacttca acagtctggg cctgggcttg taaaacctag ccaaactctg attccccaag tacaacttca acagtctggg cctgggcttg taaaacctag ccaaactctg 120 120 tccctcacgt gcgcgatttc aggggacagt gtaagttcca actcagccgo atggaactgg tccctcacgt gcgcgatttc aggggacagt gtaagttcca actcagccgc atggaactgg 180 180 atcaggcagt caccttcaag ggggctcgaa tggcttggcc gaacgtacta caggagtaag atcaggcagt caccttcaag ggggctcgaa tggcttggcc gaacgtacta caggagtaag 240 240 tggtacaacg attatgcagt gtctgtgaaa tcacggatta ctatcaatcc cgacacgtcc tggtacaacg attatgcagt gtctgtgaaa tcacggatta ctatcaatcc cgacacgtcc 300 300

aagaaccagt tctctctgca actcaactca gtgacaccag aggatacggo cgtttactat aagaaccagt tctctctgca actcaactca gtgacaccag aggatacggc cgtttactat 360 360 tgtgcacagg aagtgcaacc tgatgatgcc tttgacattt ggggtcaggg cacgatggtt tgtgcacagg aagtgcaacc tgatgatgcc tttgacattt ggggtcaggg cacgatggtt 420 420 acggtaagct ctgggggagg cggcagtgga gggggaggta gtgggggagg gggatctgat acggtaagct ctgggggagg cggcagtgga gggggaggta gtgggggagg gggatctgat 480 480 atacagatga cacaaagccc gtcatccgtc agtgcttcag ttggtgataa agtaaccatt atacagatga cacaaagccc gtcatccgtc agtgcttcag ttggtgataa agtaaccatt 540 540 acgtgccgcg cttcccaaga cgttagcgga tggttggctt ggtatcaaca aaaaccgggg acgtgccgcg cttcccaaga cgttagcgga tggttggctt ggtatcaaca aaaaccgggg 600 600 ttggctccgc aactcctcat atccggtgcg agtacgctco aaggcgaagt ccctagcaga ttggctccgc aactcctcat atccggtgcg agtacgctcc aaggcgaagt ccctagcaga 660 660

Page 101 Page 101

SequenceListing (3).txt SequenceListing (3) . txt ttttccggga gcggttccgg tacagatttc acgttgacca ttagctctct ccagcccgaa 720 ttttccggga gcggttccgg tacagatttc acgttgacca ttagctctct ccagcccgaa 720

gattttgcaa cctactattg ccaacaggcc aaaaattttc catatacatt tggtcaaggc 780 gattttgcaa cctactattg ccaacaggcc aaaaattttc catatacatt tggtcaaggc 780

actaagctcg aaatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840 actaagctcg aaatcaaagc ggccgcaact accacccctg cccctcggcc gccgactccg 840

<210> 124 <210> 124 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 124 <400> 124 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 102 Page 102

SequenceListing (3).txt SequenceListing (3) txt 35 40 45 35 40 45

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Page 103 Page 103

SequenceListing (3).txt SequenceListing (3) txt 225 230 235 240 225 230 235 240

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Page 104 Page 104

SequenceListing (3).txt SequenceListing (3) . txt 420 425 430 420 425 430

<210> 125 <210> 125 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 125 <400> 125 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 126 <210> 126 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 126 <400> 126 Gly Ala Ser Gly Ala Ser 1 1

<210> 127 <210> 127

Page 105 Page 105

<400> 127 <400> 127 Gln Gln Ala Lys Asn Phe Pro Tyr Thr Gln Gln Ala Lys Asn Phe Pro Tyr Thr 1 5 1 5

<210> 128 <210> 128 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 128 <400> 128 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 129 <210> 129 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 129 <400> 129 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 130 <210> 130 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic Page 106 Page 106

SequenceListing (3).txt SequenceListing (3) . txt peptide peptide

<400> 130 <400> 130 Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile Ala Gln Glu Val Gln Pro Asp Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 131 <210> 131 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 131 <400> 131 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacago tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60

acctgtgaca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120 acctgtgaca tctccgggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120

caagagatag aacctcatga tgcttttgat atctgggacc aagggacaat ggtcaccgtc 360 caagagatag aacctcatga tgcttttgat atctgggacc aagggacaat ggtcaccgtc 360

tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgtcatccag 420 tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgtcatccag 420

cctcagctcc tgatctctgg tgcatcctct ttgcaaggtg gagtcccatc aaggttcagc 600 cctcagctcc tgatctctgg tgcatcctct ttgcaaggtg gagtcccatc aaggttcagc 600

ctggaaatca aa 732 ctggaaatca aa 732

<210> 132 <210> 132 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence Page 107 Page 107

SequenceListing (3).txt SequenceListing (3) txt

<400> 132 <400> 132 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Thr Leu Ser Leu Thr Cys Asp Ile Ser Gly Asp Ser Val Ser Ser Asn Thr Leu Ser Leu Thr Cys Asp Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 20 25 30

Tyr Tyr Cys Ala Gln Glu Ile Glu Pro His Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Ile Glu Pro His Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Asp Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Asp Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Val Ile Gln Met Thr Gln Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Val Ile Gln Met Thr Gln Ser 130 135 140 130 135 140

Page 108 Page 108

SequenceListing (3).txt SequenceListing (3) txt

Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser Gly Ala Ser Ser Leu Gln Pro Gly Leu Ala Pro Gln Leu Leu Ile Ser Gly Ala Ser Ser Leu Gln 180 185 190 180 185 190

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 133 <210> 133 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 133 <400> 133 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60

atccctcaag tgcagctgca gcagtccggt cctggactgg tcaagccgtc ccagactctg 120 atccctcaag tgcagctgca gcagtccggt cctggactgg tcaagccgtc ccagactctg 120

agcctgactt gcgatattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180 agcctgactt gcgatattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180

atccggcagt caccatcaag gggcctggaa tggctcgggc gcacttacta ccggtccaaa 240 atccggcagt caccatcaag gggcctggaa tggctcgggc gcacttacta ccggtccaaa 240

tggtataacg actacgccgt gtccgtgaag tcccggatca ccattaaccc cgacacctcg 300 tggtataacg actacgccgt gtccgtgaag tcccggatca ccattaacco cgacacctcg 300

aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360 aagaaccagt tctcactcca actgaacago gtgacccccg aggataccgc ggtgtactac 360

tgcgcacaag aaatcgaacc gcacgacgcc ttcgacattt gggaccaggg aacgatggtc 420 tgcgcacaag aaatcgaacc gcacgacgcc ttcgacattt gggaccaggg aacgatggtc 420

acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggtg 480 acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggtg 480

Page 109 Page 109

SequenceListing (3).txt SequenceListing (3) . txt atccagatga cccagagccc ctcctcggtg tccgcatccg tgggcgataa ggtcaccatt 540 atccagatga cccagagccc ctcctcggtg tccgcatccg tgggcgataa ggtcaccatt 540

acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc 600 acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggo 600

ttggctcctc aactgctgat ctccggcgcc agctcacttc aggggggggt gccatcacgc 660 ttggctcctc aactgctgat ctccggcgcc agctcacttc aggggggggt gccatcacgc 660

ttctccggat ccggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag 720 ttctccggat ccggttccgg caccgactto accctgacca tcagcagcct ccagcctgag 720

gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc 780 gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc 780

actaagctgg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840 actaagctgg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

<210> 134 <210> 134 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 134 <400> 134 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 110 Page 110

SequenceListing (3).txt SequenceListing (3) txt

Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Asp Ile Ser Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Asp Ile Ser Gly 35 40 45 35 40 45

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Ile Glu Pro His Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Ile Glu Pro His 115 120 125 115 120 125

Asp Ala Phe Asp Ile Trp Asp Gln Gly Thr Met Val Thr Val Ser Ser Asp Ala Phe Asp Ile Trp Asp Gln Gly Thr Met Val Thr Val Ser Ser 130 135 140 130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val 145 150 155 160 145 150 155 160

Page 111 Page 111

SequenceListing (3).txt SequenceListing (3) . txt

Gly Ala Ser Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ala Ser Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser 210 215 220 210 215 220

Page 112 Page 112

SequenceListing (3).txt SequenceListing (3) . txt

<210> 135 <210> 135 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 135 <400> 135 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 136 <210> 136 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 113 Page 113

SequenceListing (3).txt SequenceListing (3) . txt <400> 136 <400> 136 Gly Ala Ser Gly Ala Ser 1 1

<210> 137 <210> 137 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 137 <400> 137 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 138 <210> 138 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 138 <400> 138 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 139 <210> 139 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 139 <400> 139 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 140 <210> 140

Page 114 Page 114

<400> 140 <400> 140 Ala Gln Glu Ile Glu Pro His Asp Ala Phe Asp Ile Ala Gln Glu Ile Glu Pro His Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 141 <210> 141 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 141 <400> 141 caagtgcagc tgcagcagtc cggtcctgga ctggtcaagc actcccagac tctgagcctg 60 caagtgcagc tgcagcagtc cggtcctgga ctggtcaagc actcccagad tctgagcctg 60

gcctgcgcga ttagcgggga ctcagtctcg tccaattcgg cggcctggaa ctggatccgg 120 gcctgcgcga ttagcgggga ctcagtctcg tccaattcgg cggcctggaa ctggatccgg 120

cagtcaccat caaggggcct ggaatggctc gggcgcactt actaccggtc caaatggtat 180 cagtcaccat caaggggcct ggaatggctc gggcgcactt actaccggtc caaatggtat 180

aacgactacg ccgtgtccgt gaagtcccgg atcaccatta accccgacac ctcgaagaac 240 aacgactacg ccgtgtccgt gaagtcccgg atcaccatta accccgacac ctcgaagaad 240

cagttctcac tccaactgaa cagcgtgacc cccgaggata ccgcggtgta ctactgcgca 300 cagttctcad tccaactgaa cagcgtgacc cccgaggata ccgcggtgta ctactgcgca 300

caagaagtgc agccgcagga cgccctggac atttgggggc agggaacgat ggtcacagtg 360 caagaagtgc agccgcagga cgccctggac atttgggggo agggaacgat ggtcacagtg 360

tcgtccggtg gaggaggttc cggaggcggt ggatctggag gcggaggttc ggatatccag 420 tcgtccggtg gaggaggttc cggaggcggt ggatctggag gcggaggtto ggatatccag 420

atgacccaga gcccctcctt cgtgtccgca tccgtgggcg ataaggtcat tattacctgt 480 atgacccaga gcccctcctt cgtgtccgca tccgtgggcg ataaggtcat tattacctgt 480

agagcgtccc aggacgtgtc cggatggctg gcctggtacc agcagaagcc aggcttggct 540 agagcgtccc aggacgtgtc cggatggctg gcctggtacc agcagaagcc aggcttggct 540

cctcaactgc tgatctccgg cgccagcact cttcaggggg aagtgccatc acgcttctcc 600 cctcaactgc tgatctccgg cgccagcact cttcaggggg aagtgccatc acgcttctcc 600

ggatccggtt ccggcaccga cttcaccctg accatcagca gcctccagcc tgaggacttc 660 ggatccggtt ccggcaccga cttcaccctg accatcagca gcctccagco tgaggactto 660

gccacttact actgccaaca ggccaagtac ttcccctata ccttcggaca aggcactaag 720 gccacttact actgccaaca ggccaagtac ttcccctata ccttcggaca aggcactaag 720

ctggaaatca ag 732 ctggaaatca ag 732

Page 115 Page 115

SequenceListing (3).txt SequenceListing (3) txt

<210> 142 <210> 142 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 142 <400> 142 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys His Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys His Ser Gln 1 5 10 15 1 5 10 15

Thr Leu Ser Leu Ala Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn Thr Leu Ser Leu Ala Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 20 25 30

Tyr Tyr Cys Ala Gln Glu Val Gln Pro Gln Asp Ala Leu Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Gln Pro Gln Asp Ala Leu Asp Ile Trp 100 105 110 100 105 110

Page 116 Page 116

SequenceListing (3).txt SequenceListing (3) txt Pro Ser Phe Val Ser Ala Ser Val Gly Asp Lys Val Ile Ile Thr Cys Pro Ser Phe Val Ser Ala Ser Val Gly Asp Lys Val Ile Ile Thr Cys 145 150 155 160 145 150 155 160

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 143 <210> 143 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 143 <400> 143 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60

atccctcaag tgcagctgca gcagtccggt cctggactgg tcaagcactc ccagactctg 120 atccctcaag tgcagctgca gcagtccggt cctggactgg tcaagcactc ccagactctg 120

agcctggcct gcgcgattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180 agcctggcct gcgcgattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180

tggtataacg actacgccgt gtccgtgaag tcccggatca ccattaaccc cgacacctcg 300 tggtataacg actacgccgt gtccgtgaag tcccggatca ccattaaccc cgacacctcg 300

Page 117 Page 117

SequenceListing (3).txt SequenceListing (3) . txt aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360 360 tgcgcacaag aagtgcagcc gcaggacgcc ctggacattt gggggcaggg aacgatggtc tgcgcacaag aagtgcagcc gcaggacgcc ctggacattt gggggcaggg aacgatggtc 420 420 acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggat acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggat 480 480 atccagatga cccagagccc ctccttcgtg tccgcatccg tgggcgataa ggtcattatt atccagatga cccagagccc ctccttcgtg tccgcatccg tgggcgataa ggtcattatt 540 540 acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc 600 600 ttggctcctc aactgctgat ctccggcgcc agcactcttc agggggaagt gccatcacgc ttggctcctc aactgctgat ctccggcgcc agcactcttc agggggaagt gccatcacgc 660 660 ttctccggat ccggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag ttctccggat ccggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag 720 720 gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc 780 780 actaagctgg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg actaagctgg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840 840 gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 900 ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960 960 ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020 1020 ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 1080 caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 1140 cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200 1200 tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 1260 cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320 1320 gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 1380 aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 1440 1440

<210> 144 <210> 144 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220> Description of Artificial Sequence: Synthetic <223> <223> Description of Artificial Sequence: Synthetic Page 118 Page 118

SequenceListing (3).txt SequenceListing (3) txt polypeptide polypeptide

<400> 144 <400> 144 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Leu Val Lys His Ser Gln Thr Leu Ser Leu Ala Cys Ala Ile Ser Gly Leu Val Lys His Ser Gln Thr Leu Ser Leu Ala Cys Ala Ile Ser Gly 35 40 45 35 40 45

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gln Glu Val Gln Pro Gln 115 120 125 115 120 125

Ile Gln Met Thr Gln Ser Pro Ser Phe Val Ser Ala Ser Val Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Val Ser Ala Ser Val Gly Asp 165 170 175 165 170 175

Lys Val Ile Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Lys Val Ile Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Gly Trp Leu Page 119 Page 119

SequenceListing (3).txt SequenceListing (3) txt 180 185 190 180 185 190

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Page 120 Page 120

SequenceListing (3).txt SequenceListing (3) . txt 370 375 380 370 375 380

<210> 145 <210> 145 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 145 <400> 145 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 146 <210> 146 <211> 3 <211> 3 <212> PRT <212> PRT

Page 121 Page 121

<400> 146 <400> 146 Gly Ala Ser Gly Ala Ser 1 1

<210> 147 <210> 147 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 147 <400> 147 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 148 <210> 148 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 148 <400> 148 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 149 <210> 149 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 122 Page 122

SequenceListing (3).txt SequenceListing (3) txt <400> 149 <400> 149 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 150 <210> 150 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 150 <400> 150 Ala Gln Glu Val Gln Pro Gln Asp Ala Leu Asp Ile Ala Gln Glu Val Gln Pro Gln Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 151 <210> 151 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 151 <400> 151 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagad cctctcacto 60

actgattatg cagtatctgt gaaaaatcga ataaccatca acccagacac atccaagaat 240 actgattatg cagtatctgt gaaaaatcga ataaccatca acccagacac atccaagaat 240

cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaacc agggctagcc 540 cgggcgagtc aggatgttag cggctggtta gcctggtatc agcagaaaco agggctagcc 540

Page 123 Page 123

SequenceListing (3).txt SequenceListing (3) . txt

ggcagtggat ctgggacaga ttttactctc accatcagta gcctgcagcc tgaagatttt 660 ggcagtggat ctgggacaga ttttactctc accatcagta gcctgcagcc tgaagatttt 660

gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggccg ggggaccaag 720 gccacttatt attgtcaaca ggctaaatat ttcccttaca cttttggccg ggggaccaag 720

ctggaaatca aa 732 ctggaaatca aa 732

<210> 152 <210> 152 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 152 <400> 152 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Thr Asp Tyr Ala Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Thr Asp Tyr Ala 50 55 60 50 55 60

Val Ser Val Lys Asn Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Val Ser Val Lys Asn Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 70 75 80

Page 124 Page 124

SequenceListing (3).txt SequenceListing (3) txt

Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Arg Gly Thr Lys Cys Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Phe Gly Arg Gly Thr Lys 225 230 235 240 225 230 235 240

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 153 <210> 153 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 153 <400> 153 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60

Page 125 Page 125

SequenceListing (3).txt SequenceListing (3) txt agcctgactt gcgcaattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180 agcctgactt gcgcaattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180

tggtataccg actacgccgt gtccgtgaag aatcggatca ccattaaccc cgacacctcg 300 tggtataccg actacgccgt gtccgtgaag aatcggatca ccattaaccc cgacacctcg 300

aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360 aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgo ggtgtactac 360

tgcgcacaag aagtggaacc gcaggacgcc ttcgacattt ggggacaggg aacgatggtc 420 tgcgcacaag aagtggaacc gcaggacgcc ttcgacattt ggggacaggg aacgatggto 420

acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggat 480 acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggat 480

atccagatga cccagagccc ctcctcggtg tccgcatccg tgggcgataa ggtcaccatt 540 atccagatga cccagagccc ctcctcggtg tccgcatccg tgggcgataa ggtcaccatt 540

acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc 600 acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc 600

ttggctcctc aactgctgat cttcggcgcc agcactcttc agggggaagt gccatcacgc 660 ttggctcctc aactgctgat cttcggcgcc agcactctto agggggaagt gccatcacgc 660

ttctccggat ccggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag 720 ttctccggat ccggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag 720

gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggaagaggc 780 gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggaagaggc 780

<210> 154 <210> 154

Page 126 Page 126

<400> 154 <400> 154 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Trp Tyr Thr Asp Tyr Ala Val Ser Val Lys Asn Arg Ile Thr Ile Asn Trp Tyr Thr Asp Tyr Ala Val Ser Val Lys Asn Arg Ile Thr Ile Asn 85 90 95 85 90 95

Page 127 Page 127

SequenceListing (3).txt SequenceListing (3) txt

Phe Gly Arg Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr Phe Gly Arg Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Thr Thr 260 265 270 260 265 270

Page 128 Page 128

SequenceListing (3).txt SequenceListing (3) . txt

<210> 155 <210> 155 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 155 <400> 155 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp Page 129 Page 129

SequenceListing (3).txt SequenceListing (3) txt 1 5 1 5

<210> 156 <210> 156 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 156 <400> 156 Gly Ala Ser Gly Ala Ser 1 1

<210> 157 <210> 157 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 157 <400> 157 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 158 <210> 158 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 158 <400> 158 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 159 <210> 159 <211> 9 <211> 9 <212> PRT <212> PRT

Page 130 Page 130

<400> 159 <400> 159 Thr Tyr Tyr Arg Ser Lys Trp Tyr Thr Thr Tyr Tyr Arg Ser Lys Trp Tyr Thr 1 5 1 5

<210> 160 <210> 160 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 160 <400> 160 Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 161 <210> 161 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 161 <400> 161 caggtacago tgcagcagtc aggtccagga ctggtgaago cctcgcagad cctctcactc caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 60

acctgtgcca tctcagggaa cagtgtctct agcaacagtg ctgcttggaa ctggatcagg acctgtgcca tctcagggaa cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120 120

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180 180

aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacao atccaagaad aatgattatg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240 240

caagaggtag aacctcaaga tgcttttgat atctggggcc aagggacaat ggtcaccgtc caagaggtag aacctcaaga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360 360

tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgacatccag tcttcaggag gtggcgggtc tggcggtgga ggtagcggtg gtggcggatc cgacatccag 420 420

Page 131 Page 131

SequenceListing (3).txt SequenceListing (3) . txt

atgacccagt ctccatcttc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480 atgacccagt ctccatctto cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480

cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccatc aagattcagc 600 cctcagctcc tgatctttgg tgcatccact ttgcaaggtg aagtcccatc aagattcagc 600

ggcggtggat ctgggacaga ttttactctc accatcagca gcctgcagcc tgaagatttt 660 ggcggtggat ctgggacaga ttttactctc accatcagca gcctgcagcc tgaagatttt 660

ctggaaatca aa 732 ctggaaatca aa 732

<210> 162 <210> 162 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 162 <400> 162 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asn Ser Val Ser Ser Asn Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asn Ser Val Ser Ser Asn 20 25 30 20 25 30

Page 132 Page 132

SequenceListing (3).txt SequenceListing (3) txt Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Trp Tyr Tyr Cys Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Trp 100 105 110 100 105 110

Gly Glu Val Pro Ser Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe Gly Glu Val Pro Ser Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe 195 200 205 195 200 205

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 163 <210> 163 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 133 Page 133

SequenceListing (3).txt 7x7 (E)

<400> 163 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60 09

atccctcaag tgcagctgca gcagtccggt cctggactgg tcaagccgtc ccagactctg 120 OZI

agcctgactt gcgccattag cgggaactca gtctcgtcca attcggcggc ctggaactgg 180 08D

atccggcagt caccatcaag gggcctggaa tggctcgggc gcacttacta ccggtccaaa 240

tggtataacg actacgccgt gtccgtgaag tcccggatca ccattaaccc cgacacctcg 300 00E

aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360 09E

tgcgcacaag aagtggaacc gcaggacgcc ttcgacattt ggggacaggg aacgatggtc 420

acagtgtcgt ccggtggagg aggttccgga ggcggtggat ctggaggcgg aggttcggat 480 08/

atccagatga cccagagccc ctcctcggtg tccgcatccg tgggcgataa ggtcaccatt 540

acctgtagag cgtcccagga cgtgtccgga tggctggcct ggtaccagca gaagccaggc 600 009

ttggctcctc aactgctgat ctttggcgcc agcactcttc agggggaggt gccatcacgc 660 099

ttctccggag gtggttccgg caccgacttc accctgacca tcagcagcct ccagcctgag 720 OZL

gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc 780 08L

actaagctgg aaatcaaggc ggccgcaact accacccctg cccctcggcc gccgactccg 840

gccccaacca tcgcaagcca acccctctcc ttgcgccccg aagcttgccg cccggccgcg 900 006

ggtggagccg tgcatacccg ggggctggac tttgcctgcg atatctacat ttgggccccg 960 096

ctggccggca cttgcggcgt gctcctgctg tcgctggtca tcacccttta ctgcaagagg 1020 0201

ggccggaaga agctgcttta catcttcaag cagccgttca tgcggcccgt gcagacgact 1080 080I

caggaagagg acggatgctc gtgcagattc cctgaggagg aagagggggg atgcgaactg 1140 999999e8ee

cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 1200

tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 097I

cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 1320 OZET

gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 1380 08ET

Page 134 DEI aged

<210> 164 <210> 164 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 164 <400> 164 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Asn Ser Val Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Asn Ser Val Ser Ser Asn Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser 50 55 60 50 55 60

Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Page 135 Page 135

SequenceListing (3).txt SequenceListing (3) txt 130 135 140 130 135 140

Gly Ala Ser Thr Leu Gln Gly Glu Val Pro Ser Arg Phe Ser Gly Gly Gly Ala Ser Thr Leu Gln Gly Glu Val Pro Ser Arg Phe Ser Gly Gly 210 215 220 210 215 220

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Page 136 Page 136

SequenceListing (3).txt SequenceListing (3) . txt 325 330 335 325 330 335

<210> 165 <210> 165 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 137 Page 137

<400> 165 <400> 165 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 166 <210> 166 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 166 <400> 166 Gly Ala Ser Gly Ala Ser 1 1

<210> 167 <210> 167 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 167 <400> 167 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 168 <210> 168 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 168 <400> 168 Gly Asn Ser Val Ser Ser Asn Ser Ala Ala Gly Asn Ser Val Ser Ser Asn Ser Ala Ala Page 138 Page 138

SequenceListing (3).txt SequenceListing (3) . txt 1 5 10 1 5 10

<210> 169 <210> 169 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 169 <400> 169 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 170 <210> 170 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 170 <400> 170 Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile Ala Gln Glu Val Glu Pro Gln Asp Ala Phe Asp Ile 1 5 10 1 5 10

<210> 171 <210> 171 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 171 <400> 171 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60 caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagad cctctcactc 60

Page 139 Page 139

SequenceListing (3).txt SequenceListing (3) . txt

atgacgcagt ctccatcatc cgtgtctgca tctgtaggag acaaagtcac catcacttgt 480 atgacgcagt ctccatcatc cgtgtctgca tctgtaggag acaaagtcad catcacttgt 480

cgggcgagtc aggatgttag cggctggtta gcctggtatc aacagaaacc agggctagcc 540 cgggcgagtc aggatgttag cggctggtta gcctggtato aacagaaaco agggctagcc 540

ctggagatca aa 732 ctggagatca aa 732

<210> 172 <210> 172 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 172 <400> 172 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 1 5 10 15

Page 140 Page 140

SequenceListing (3).txt SequenceListing (3) txt

Leu Glu Ile Lys Leu Glu Ile Lys

<210> 173 <210> 173 <211> 1476 <211> 1476

Page 141 Page 141

SequenceListing (3).txt SequenceListing (3) txt <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 173 <400> 173 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60 atgttgctgc tcgtgacctc gctccttctg tgcgagctgc cccatccggc ttttctgctc 60

agcctgactt gcgcgattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180 agcctgactt gcgcgattag cggggactca gtctcgtcca attcggcggc ctggaactgg 180

aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360 aagaaccagt tctcactcca actgaacagc gtgacccccg aggataccgc ggtgtactac 360

tgcgcacaag aagtggaacc gcacgacgcc ctggacattt ggggtcaggg aacgatggtc 420 tgcgcacaag aagtggaacc gcacgacgcc ctggacattt ggggtcaggg aacgatggto 420

ttggctcctc aactgctgat cttcggcgcc agcacacttc agggggaggt gccatcacgc 660 ttggctcctc aactgctgat cttcggcgcc agcacactto agggggaggt gccatcacgc 660

gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggc 780 gacttcgcca cttactactg ccaacaggcc aagtacttcc cctatacctt cggacaaggo 780

Page 142 Page 142

SequenceListing (3).txt SequenceListing (3) . txt tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260 tacaaccage tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 1260

<210> 174 <210> 174 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 174 <400> 174 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 143 Page 143

SequenceListing (3).txt SequenceListing (3) txt

Page 144 Page 144

SequenceListing (3).txt SequenceListing (3) . txt

Page 145 Page 145

SequenceListing (3).txt SequenceListing (3) txt

<210> 175 <210> 175 <211> 6 <211> 6 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 175 <400> 175 Gln Asp Val Ser Gly Trp Gln Asp Val Ser Gly Trp 1 5 1 5

<210> 176 <210> 176 <211> 3 <211> 3 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 176 <400> 176 Gly Ala Ser Gly Ala Ser 1 1

<210> 177 <210> 177 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 177 <400> 177 Gln Gln Ala Lys Tyr Phe Pro Tyr Thr Gln Gln Ala Lys Tyr Phe Pro Tyr Thr 1 5 1 5

<210> 178 <210> 178 <211> 10 <211> 10 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 146 Page 146

<400> 178 <400> 178 Gly Asp Ser Val Ser Ser Asn Ser Ala Ala Gly Asp Ser Val Ser Ser Asn Ser Ala Ala 1 5 10 1 5 10

<210> 179 <210> 179 <211> 9 <211> 9 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 179 <400> 179 Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn 1 5 1 5

<210> 180 <210> 180 <211> 12 <211> 12 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 180 <400> 180 Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile Ala Gln Glu Val Glu Pro His Asp Ala Leu Asp Ile 1 5 10 1 5 10

<210> 181 <210> 181 <211> 66 <211> 66 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<220> <220> <223> Description of Artificial Sequence: Synthetic <223> Description of Artificial Sequence: Synthetic oligonucleotide oligonucleotide

<400> 181 <400> 181 atttgggccc cgctggccgg cacttgcggc gtgctcctgc tgtcgctggt catcaccctt 60 atttgggccc cgctggccgg cacttgcggc gtgctcctgc tgtcgctggt catcaccctt 60

Page 147 Page 147

SequenceListing (3).txt SequenceListing (3) txt

tactgc 66 tactgc 66

<210> 182 <210> 182 <211> 22 <211> 22 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 182 <400> 182 Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 1 5 10 15 1 5 10 15

Val Ile Thr Leu Tyr Cys Val Ile Thr Leu Tyr Cys 20 20

<210> 183 <210> 183 <211> 141 <211> 141 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 183 <400> 183 actaccaccc ctgcccctcg gccgccgact ccggccccaa ccatcgcaag ccaacccctc 60 actaccaccc ctgcccctcg gccgccgact ccggccccaa ccatcgcaag ccaacccctc 60

tccttgcgcc ccgaagcttg ccgcccggcc gcgggtggag ccgtgcatac ccgggggctg 120 tccttgcgcc ccgaagcttg ccgcccggcc gcgggtggag ccgtgcatac ccgggggctg 120

gactttgcct gcgatatcta c 141 gactttgcct gcgatatcta C 141

<210> 184 <210> 184 <211> 47 <211> 47 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

Page 148 Page 148

SequenceListing (3).txt SequenceListing (3) . txt <400> 184 <400> 184 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 1 5 10 15 1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 20 25 30 20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 35 40 45 35 40 45

<210> 185 <210> 185 <211> 69 <211> 69 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 185 <400> 185 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 1 5 10 15 1 5 10 15

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 35 40 45 35 40 45

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val 50 55 60 50 55 60

Ile Thr Leu Tyr Cys Ile Thr Leu Tyr Cys

<210> 186 <210> 186 <211> 126 <211> 126 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 149 Page 149

<400> 186 <400> 186 aagaggggcc ggaagaagct gctttacatc ttcaagcagc cgttcatgcg gcccgtgcag 60 aagaggggcc ggaagaagct gctttacatc ttcaagcagc cgttcatgcg gcccgtgcag 60

acgactcagg aagaggacgg atgctcgtgc agattccctg aggaggaaga ggggggatgc 120 acgactcagg aagaggacgg atgctcgtgc agattccctg aggaggaaga ggggggatgo 120

gaactg 126 gaactg 126

<210> 187 <210> 187 <211> 42 <211> 42 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 187 <400> 187 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 35 40

<210> 188 <210> 188 <211> 336 <211> 336 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 188 <400> 188 cgcgtcaagt tctcacggtc cgccgacgcc cccgcatatc aacagggcca gaatcagctc 60 cgcgtcaagt tctcacggtc cgccgacgcc cccgcatato aacagggcca gaatcagctc 60

tacaacgagc tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 120 tacaacgago tgaacctggg aaggagagag gagtacgacg tgctggacaa gcgacgcgga 120

Page 150 Page 150

SequenceListing (3).txt SequenceListing (3) . txt cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 180 cgcgacccgg agatgggggg gaaaccacgg cggaaaaacc ctcaggaagg actgtacaac 180

gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 240 gaactccaga aagacaagat ggcggaagcc tactcagaaa tcgggatgaa gggagagcgg 240

aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 300 aggaggggaa agggtcacga cgggctgtac cagggactga gcaccgccac taaggatacc 300

tacgatgcct tgcatatgca agcactccca ccccgg 336 tacgatgcct tgcatatgca agcactccca ccccgg 336

<210> 189 <210> 189 <211> 112 <211> 112 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 189 <400> 189 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 50 55 60 50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 65 70 75 80 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 85 90 95 85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 100 105 110 100 105 110

<210> 190 <210> 190

Page 151 Page 151

SequenceListing (3).txt SequenceListing (3) . txt <211> 66 <211> 66 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 190 <400> 190 atgctgctgc tggtgaccag cctgctgctg tgcgaactgc cgcatccggc gtttctgctg 60 atgctgctgc tggtgaccag cctgctgctg tgcgaactgo cgcatccggc gtttctgctg 60

attccg 66 attccg 66

<210> 191 <210> 191 <211> 22 <211> 22 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 191 <400> 191 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Ala Phe Leu Leu Ile Pro Ala Phe Leu Leu Ile Pro 20 20

<210> 192 <210> 192 <211> 726 <211> 726 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 192 <400> 192 gacattcaga tgactcagac cacctcttcc ttgtccgcgt cactgggaga cagagtgacc 60 gacattcaga tgactcagac cacctcttcc ttgtccgcgt cactgggaga cagagtgacc 60

atctcgtgtc gcgcaagcca ggatatctcc aagtacctga actggtacca acagaagccc 120 atctcgtgtc gcgcaagcca ggatatctcc aagtacctga actggtacca acagaagccc 120

gacgggactg tgaagctgct gatctaccac acctcacgcc tgcacagcgg agtgccaagc 180 gacgggactg tgaagctgct gatctaccac acctcacgcc tgcacagcgg agtgccaagc 180

Page 152 Page 152

SequenceListing (3).txt SequenceListing (3) txt agattctccg gctccggctc gggaaccgat tactcgctta ccattagcaa cctcgagcag 240 agattctccg gctccggctc gggaaccgat tactcgctta ccattagcaa cctcgagcag 240

gaggacatcg ctacctactt ctgccagcaa ggaaataccc tgccctacac cttcggcgga 300 gaggacatcg ctacctactt ctgccagcaa ggaaatacco tgccctacac cttcggcgga 300

ggaaccaaat tggaaatcac cggcggagga ggctccgggg gaggaggttc cgggggcggg 360 ggaaccaaat tggaaatcad cggcggagga ggctccgggg gaggaggtto cgggggcggg 360

ggttccgaag tgaagctcca ggagtccggc cccggcctgg tggcgccgtc gcaatcactc 420 ggttccgaag tgaagctcca ggagtccggc cccggcctgg tggcgccgtc gcaatcactc 420

tctgtgacct gtaccgtgtc gggagtgtcc ctgcctgatt acggcgtgag ctggattcgg 480 tctgtgacct gtaccgtgtc gggagtgtcc ctgcctgatt acggcgtgag ctggattcgg 480

cagccgccgc ggaagggcct ggaatggctg ggtgtcatct ggggatccga gactacctac 540 cagccgccgc ggaagggcct ggaatggctg ggtgtcatct ggggatccga gactacctad 540

tacaactcgg ccctgaagtc ccgcctgact atcatcaaag acaactcgaa gtcccaggtc 600 tacaactcgg ccctgaagtc ccgcctgact atcatcaaag acaactcgaa gtcccaggto 600

tttctgaaga tgaactccct gcaaactgac gacaccgcca tctattactg tgctaagcac 660 tttctgaaga tgaactccct gcaaactgad gacaccgcca tctattactg tgctaagcad 660

tactactacg gtggaagcta tgctatggac tactgggggc aaggcacttc ggtgactgtg 720 tactactacg gtggaagcta tgctatggac tactgggggo aaggcactto ggtgactgtg 720

tcaagc 726 tcaagc 726

<210> 193 <210> 193 <211> 242 <211> 242 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 193 <400> 193 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr 20 25 30 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

Page 153 Page 153

SequenceListing (3).txt SequenceListing (3) txt 65 70 75 80 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr 85 90 95 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser 100 105 110 100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu 115 120 125 115 120 125

Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys 130 135 140 130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg 145 150 155 160 145 150 155 160

Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser 165 170 175 165 170 175

Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile 180 185 190 180 185 190

Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln 195 200 205 195 200 205

Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly 210 215 220 210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val 225 230 235 240 225 230 235 240

Ser Ser Ser Ser

<210> 194 <210> 194

Page 154 Page 154

SequenceListing (3).txt SequenceListing (3) txt <211> 1470 <211> 1470 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 194 <400> 194 atgcttctcc tggtcacctc cctgctcctc tgcgaactgc ctcaccctgc cttccttctg 60 atgcttctcc tggtcacctc cctgctcctc tgcgaactgc ctcaccctgc cttccttctg 60

attcctgaca ttcagatgac tcagaccacc tcttccttgt ccgcgtcact gggagacaga 120 attcctgaca ttcagatgac tcagaccacc tcttccttgt ccgcgtcact gggagacaga 120

gtgaccatct cgtgtcgcgc aagccaggat atctccaagt acctgaactg gtaccaacag 180 gtgaccatct cgtgtcgcgc aagccaggat atctccaagt acctgaactg gtaccaacag 180

aagcccgacg ggactgtgaa gctgctgatc taccacacct cacgcctgca cagcggagtg 240 aagcccgacg ggactgtgaa gctgctgatc taccacacct cacgcctgca cagcggagtg 240

ccaagcagat tctccggctc cggctcggga accgattact cgcttaccat tagcaacctc 300 ccaagcagat tctccggctc cggctcggga accgattact cgcttaccat tagcaacctc 300

gagcaggagg acatcgctac ctacttctgc cagcaaggaa ataccctgcc ctacaccttc 360 gagcaggagg acatcgctac ctacttctgc cagcaaggaa ataccctgcc ctacaccttc 360

ggcggaggaa ccaaattgga aatcaccggc ggaggaggct ccgggggagg aggttccggg 420 ggcggaggaa ccaaattgga aatcaccggc ggaggaggct ccgggggagg aggttccggg 420

ggcgggggtt ccgaagtgaa gctccaggag tccggccccg gcctggtggc gccgtcgcaa 480 ggcgggggtt ccgaagtgaa gctccaggag tccggccccg gcctggtggc gccgtcgcaa 480

tcactctctg tgacctgtac cgtgtcggga gtgtccctgc ctgattacgg cgtgagctgg 540 tcactctctg tgacctgtac cgtgtcggga gtgtccctgc ctgattacgg cgtgagctgg 540

attcggcagc cgccgcggaa gggcctggaa tggctgggtg tcatctgggg atccgagact 600 attcggcagc cgccgcggaa gggcctggaa tggctgggtg tcatctgggg atccgagact 600

acctactaca actcggccct gaagtcccgc ctgactatca tcaaagacaa ctcgaagtcc 660 acctactaca actcggccct gaagtcccgc ctgactatca tcaaagacaa ctcgaagtcc 660

caggtctttc tgaagatgaa ctccctgcaa actgacgaca ccgccatcta ttactgtgct 720 caggtctttc tgaagatgaa ctccctgcaa actgacgaca ccgccatcta ttactgtgct 720

aagcactact actacggtgg aagctatgct atggactact gggggcaagg cacttcggtg 780 aagcactact actacggtgg aagctatgct atggactact gggggcaagg cacttcggtg 780

actgtgtcaa gcgcggccgc aactaccacc cctgcccctc ggccgccgac tccggcccca 840 actgtgtcaa gcgcggccgc aactaccaco cctgcccctc ggccgccgac tccggcccca 840

Page 155 Page 155

SequenceListing (3).txt SequenceListing (3) . txt

gagctgaacc tgggaaggag agaggagtac gacgtgctgg acaagcgacg cggacgcgac 1260 gagctgaacc tgggaaggag agaggagtad gacgtgctgg acaagcgacg cggacgcgac 1260

ccggagatgg gggggaaacc acggcggaaa aaccctcagg aaggactgta caacgaactc 1320 ccggagatgg gggggaaacc acggcggaaa aaccctcagg aaggactgta caacgaactc 1320

gccttgcata tgcaagcact cccaccccgg 1470 gccttgcata tgcaagcact cccaccccgg 1470

<210> 195 <210> 195 <211> 490 <211> 490 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 195 <400> 195 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser 20 25 30 20 25 30

Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser 35 40 45 35 40 45

Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly 50 55 60 50 55 60

Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val 65 70 75 80 70 75 80

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr 85 90 95 85 90 95

Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln 100 105 110 100 105 110

Page 156 Page 156

SequenceListing (3).txt SequenceListing (3) txt

Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 115 120 125 115 120 125

Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 130 135 140

Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 145 150 155 160 145 150 155 160

Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 165 170 175 165 170 175

Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu 180 185 190 180 185 190

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys 195 200 205 195 200 205

Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 210 215 220 210 215 220

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 225 230 235 240 225 230 235 240

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln 245 250 255 245 250 255

Gly Thr Ser Val Thr Val Ser Ser Ala Ala Ala Thr Thr Thr Pro Ala Gly Thr Ser Val Thr Val Ser Ser Ala Ala Ala Thr Thr Thr Pro Ala 260 265 270 260 265 270

Page 157 Page 157

SequenceListing (3).txt SequenceListing (3) . txt

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 420 425 430 420 425 430

Page 158 Page 158

SequenceListing (3).txt SequenceListing (3) txt

<210> 196 <210> 196 <211> 1482 <211> 1482 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 196 <400> 196 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60 atgcttcttt tggtgacttc ccttttgctg tgcgagttgc cacaccccgc cttcctgctt 60

attccccagg tacagctcca gcagagtggc ccagggctcg tgaagccaag ccagacgctg 120 attccccagg tacagctcca gcagagtggc ccagggctcg tgaagccaag ccagacgctg 120

tccctgactt gtgcaatttc aggggattca gtttcatcaa atagcgcggc gtggaattgg 180 tccctgactt gtgcaatttc aggggattca gtttcatcaa atagcgcggc gtggaattgg 180

attcgacaat ctccttcccg agggttggaa tggcttggac gaacatatta cagatccaaa 240 attcgacaat ctccttcccg agggttggaa tggcttggac gaacatatta cagatccaaa 240

tggtataacg actatgcggt atcagtaaag tcaagaataa ccattaaccc cgacacaagc 300 tggtataacg actatgcggt atcagtaaag tcaagaataa ccattaaccc cgacacaagc 300

aagaaccaat tctctttgca gcttaactct gtcacgccag aagacacggc agtctattat 360 aagaaccaat tctctttgca gcttaactct gtcacgccag aagacacggc agtctattat 360

tgcgctcgcg aggtaacggg tgacctggaa gacgcttttg acatttgggg gcagggtacg 420 tgcgctcgcg aggtaacggg tgacctggaa gacgcttttg acatttgggg gcagggtacg 420

atggtgacag tcagttcagg gggcggtggg agtgggggag ggggtagcgg ggggggaggg 480 atggtgacag tcagttcagg gggcggtggg agtgggggag ggggtagcgg ggggggaggg 480

tcagacattc agatgaccca gtccccttca tccttgtctg cctccgtcgg tgacagggtg 540 tcagacattc agatgaccca gtccccttca tccttgtctg cctccgtcgg tgacagggtg 540

acaataacat gcagagcaag ccaaacaatc tggagctatc tcaactggta ccagcagcga 600 acaataacat gcagagcaag ccaaacaatc tggagctatc tcaactggta ccagcagcga 600

ccaggaaaag cgccaaacct gctgatttac gctgcttcct ccctccaatc aggcgtgcct 660 ccaggaaaag cgccaaacct gctgatttac gctgcttcct ccctccaatc aggcgtgcct 660

agtagattta gcggtagggg ctccggcacc gattttacgc tcactataag ctctcttcaa 720 agtagattta gcggtagggg ctccggcacc gattttacgc tcactataag ctctcttcaa 720

gcagaagatt ttgcgactta ttactgccag cagtcctata gtatacctca gactttcgga 780 gcagaagatt ttgcgactta ttactgccag cagtcctata gtatacctca gactttcgga 780

cagggtacca agttggagat taaggcggcc gcaactacca cccctgcccc tcggccgccg 840 cagggtacca agttggagat taaggcggcc gcaactacca cccctgcccc tcggccgccg 840

actccggccc caaccatcgc aagccaaccc ctctccttgc gccccgaagc ttgccgcccg 900 actccggccc caaccatcgc aagccaaccc ctctccttgc gccccgaagc ttgccgcccg 900

gccgcgggtg gagccgtgca tacccggggg ctggactttg cctgcgatat ctacatttgg 960 gccgcgggtg gagccgtgca tacccggggg ctggactttg cctgcgatat ctacatttgg 960

gccccgctgg ccggcacttg cggcgtgctc ctgctgtcgc tggtcatcac cctttactgc 1020 gccccgctgg ccggcacttg cggcgtgctc ctgctgtcgc tggtcatcac cctttactgc 1020

aagaggggcc ggaagaagct gctttacatc ttcaagcagc cgttcatgcg gcccgtgcag 1080 aagaggggcc ggaagaagct gctttacatc ttcaagcagc cgttcatgcg gcccgtgcag 1080

Page 159 Page 159

SequenceListing (3).txt SequenceListing (3) txt acgactcagg aagaggacgg atgctcgtgc agattccctg aggaggaaga ggggggatgc 1140 acgactcagg aagaggacgg atgctcgtgc agattccctg aggaggaaga ggggggatgo 1140

gaactgcgcg tcaagttctc acggtccgcc gacgcccccg catatcaaca gggccagaat 1200 gaactgcgcg tcaagttctc acggtccgcc gacgcccccg catatcaaca gggccagaat 1200

cagctctaca acgagctgaa cctgggaagg agagaggagt acgacgtgct ggacaagcga 1260 cagctctaca acgagctgaa cctgggaagg agagaggagt acgacgtgct ggacaagcga 1260

cgcggacgcg acccggagat gggggggaaa ccacggcgga aaaaccctca ggaaggactg 1320 cgcggacgcg acccggagat gggggggaaa ccacggcgga aaaaccctca ggaaggactg 1320

tacaacgaac tccagaaaga caagatggcg gaagcctact cagaaatcgg gatgaaggga 1380 tacaacgaac tccagaaaga caagatggcg gaagcctact cagaaatcgg gatgaaggga 1380

gagcggagga ggggaaaggg tcacgacggg ctgtaccagg gactgagcac cgccactaag 1440 gagcggagga ggggaaaggg tcacgacggg ctgtaccagg gactgagcac cgccactaag 1440

gatacctacg atgccttgca tatgcaagca ctcccacccc gg 1482 gatacctacg atgccttgca tatgcaagca ctcccacccc gg 1482

<210> 197 <210> 197 <211> 494 <211> 494 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 197 <400> 197 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Page 160 Page 160

SequenceListing (3).txt SequenceListing (3) txt

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Val Thr Gly Asp Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Val Thr Gly Asp 115 120 125 115 120 125

Leu Glu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Leu Glu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 130 135 140 130 135 140

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 145 150 155 160 145 150 155 160

Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val 165 170 175 165 170 175

Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Trp Ser Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Trp Ser 180 185 190 180 185 190

Tyr Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Tyr Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu 195 200 205 195 200 205

Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser 210 215 220 210 215 220

Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 225 230 235 240 225 230 235 240

Ala Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Ala Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro 245 250 255 245 250 255

Gln Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr Gln Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ala Ala Ala Thr 260 265 270 260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 275 280 285 275 280 285

Page 161 Page 161

SequenceListing (3).txt SequenceListing (3) . txt

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 290 295 300 290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 305 310 315 320 305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 325 330 335 325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys 340 345 350 340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys 355 360 365 355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val 370 375 380 370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 385 390 395 400 385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 405 410 415 405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 420 425 430 420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 435 440 445 435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 450 455 460 450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 465 470 475 480 465 470 475 480

Page 162 Page 162

SequenceListing (3).txt SequenceListing (3) . txt

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 485 490

<210> 198 <210> 198 <211> 732 <211> 732 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 198 <400> 198 gaggtccagc tggtacagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 gaggtccagc tggtacagtc tgggggaggc ttggtacago ctggggggto cctgagacto 60

tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120

ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180

gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 gcggactctg tgaagggccg attcaccato tccagagaca acgccaagaa ctccctgtat 240

ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagattta 300 ctgcaaatga acagtctgag agctgaggad acggccttgt attactgtgo aaaagattta 300

tcgtcagtgg ctggaccctt taactactgg ggccagggca ccctggtcac cgtctcctca 360 tcgtcagtgg ctggaccctt taactactgg ggccagggca ccctggtcac cgtctcctca 360

ggaggtggcg ggtctggtgg aggcggtagc ggcggtggcg gatcctcttc tgagctgact 420 ggaggtggcg ggtctggtgg aggcggtago ggcggtggcg gatcctcttc tgagctgact 420

caggaccctg ctgtgtctgt ggccttggga cagacagtca ggatcacatg ccaaggagac 480 caggaccctg ctgtgtctgt ggccttggga cagacagtca ggatcacatg ccaaggagad 480

agcctcagaa gctattatgc aagctggtac cagcagaagc caggacaggc ccctgtactt 540 agcctcagaa gctattatgo aagctggtac cagcagaage caggacaggc ccctgtactt 540

gtcatctatg gtaaaaacaa ccggccctca gggatcccag accgattctc tggctccagc 600 gtcatctatg gtaaaaacaa ccggccctca gggatcccag accgattctc tggctccago 600

tcaggaaaca cagcttcctt gaccatcact ggggctcagg cggaggatga ggctgactat 660 tcaggaaaca cagcttcctt gaccatcact ggggctcagg cggaggatga ggctgactat 660

tactgtaact cccgggacag cagtggtaac catctggtat tcggcggagg cacccagctg 720 tactgtaact cccgggacag cagtggtaac catctggtat tcggcggagg cacccagctg 720

accgtcctcg gt 732 accgtcctcg gt 732

<210> 199 <210> 199 <211> 244 <211> 244 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<220> <220>

Page 163 Page 163

SequenceListing (3).txt SequenceListing (3) . txt <223> Description of Artificial Sequence: Synthetic < 223> Description of Artificial Sequence: Synthetic polypeptide polypeptide

<400> 199 <400> 199 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 35 40 45

Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 85 90 95

Ala Lys Asp Leu Ser Ser Val Ala Gly Pro Phe Asn Tyr Trp Gly Gln Ala Lys Asp Leu Ser Ser Val Ala Gly Pro Phe Asn Tyr Trp Gly Gln 100 105 110 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 115 120 125

Gly Ser Gly Gly Gly Gly Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Gly Ser Gly Gly Gly Gly Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala 130 135 140 130 135 140

Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp 145 150 155 160 145 150 155 160

Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln 165 170 175 165 170 175

Page 164 Page 164

SequenceListing (3)Pro . txt SequenceListing (3).txt Ala Pro Val 180 Leu Val Ile Tyr Gly Lys Asn Asn Arg Ser Gly Ile Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile 180 185 190 185 190

Pro Asp Arg 195 Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr 195 200 205 200 205

Ile Thr 210 Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser 210 215 220 215 220

Arg 225 Asp Ser Ser Gly Asn His Leu Val Phe Gly Gly Gly Thr Gln Leu Arg Asp Ser Ser Gly Asn His Leu Val Phe Gly Gly Gly Thr Gln Leu 225 230 235 240 230 235 240

Thr Val Leu Gly Thr Val Leu Gly

<210> 200 <210> 200 <211> 1476 <211> 1476 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<220> <220> Description of Artificial Sequence: Synthetic <223> <223> Description of Artificial Sequence: Synthetic polynucleotide polynucleotide

<400> 200 <400> 200 atgctgctgc tggtgaccag cctgctgctg tgcgaactgc cgcatccggc gtttctgctg atgctgctgc tggtgaccag cctgctgctg tgcgaactgc cgcatccggc gtttctgctg 60 60 attccggagg tccagctggt acagtctggg ggaggcttgg tacagcctgg ggggtccctg attccggagg tccagctggt acagtctggg ggaggcttgg tacagcctgg ggggtccctg 120 120 agactctcct gtgcagcctc tggattcacc tttgatgatt atgccatgca ctgggtccgg agactctcct gtgcagcctc tggattcacc tttgatgatt atgccatgca ctgggtccgg 180 180 caagctccag ggaagggcct ggagtgggtc tcaggtatta gttggaatag tggtagcata caagctccag ggaagggcct ggagtgggtc tcaggtatta gttggaatag tggtagcata 240 240 ggctatgcgg actctgtgaa gggccgattc accatctcca gagacaacgo caagaactcc ggctatgcgg actctgtgaa gggccgattc accatctcca gagacaacgc caagaactcc 300 300 ctgtatctgc aaatgaacag tctgagagct gaggacacgg ccttgtatta ctgtgcaaaa ctgtatctgc aaatgaacag tctgagagct gaggacacgg ccttgtatta ctgtgcaaaa 360 360 gatttatcgt cagtggctgg accctttaac tactggggcc agggcacct ggtcaccgtc gatttatcgt cagtggctgg accctttaac tactggggcc agggcaccct ggtcaccgtc 420 420 tcctcaggag gtggcgggtc tggtggaggc ggtagcggcg gtggcggatc ctcttctgag tcctcaggag gtggcgggtc tggtggaggc ggtagcggcg gtggcggatc ctcttctgag 480 480 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 540 540

Page 165 Page 165

SequenceListing (3).txt SequenceListing (3) txt ggagacagcc tcagaagcta ttatgcaagc tggtaccagc agaagccagg acaggcccct 600 ggagacagcc tcagaagcta ttatgcaagc tggtaccagc agaagccagg acaggcccct 600

gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 660 gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 660

tccagctcag gaaacacagc ttccttgacc atcactgggg ctcaggcgga ggatgaggct 720 tccagctcag gaaacacago ttccttgacc atcactgggg ctcaggcgga ggatgaggct 720

gactattact gtaactcccg ggacagcagt ggtaaccatc tggtattcgg cggaggcacc 780 gactattact gtaactcccg ggacagcagt ggtaaccatc tggtattcgg cggaggcacc 780

cagctgaccg tcctcggtgc ggccgcaact accacccctg cccctcggcc gccgactccg 840 cagctgaccg tcctcggtgc ggccgcaact accacccctg cccctcggcc gccgactccg 840

<210> 201 <210> 201 <211> 492 <211> 492 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 201 <400> 201 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Gln Ser Gly Gly Gly Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Gln Ser Gly Gly Gly Page 166 Page 166

SequenceListing (3).txt SequenceListing (3) txt 20 25 30 20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 35 40 45

Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly 50 55 60 50 55 60

Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile 65 70 75 80 70 75 80

Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 85 90 95

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 100 105 110

Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Leu Ser Ser Val Ala Gly Pro Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Leu Ser Ser Val Ala Gly Pro 115 120 125 115 120 125

Phe Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 130 135 140 130 135 140

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser Glu Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser Glu 145 150 155 160 145 150 155 160

Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg 165 170 175 165 170 175

Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr 180 185 190 180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn 195 200 205 195 200 205

Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Page 167 Page 167

SequenceListing (3).txt SequenceListing (3) . txt 210 215 220 210 215 220

Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala 225 230 235 240 225 230 235 240

Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Leu Val Phe Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Leu Val Phe 245 250 255 245 250 255

Gly Gly Gly Thr Gln Leu Thr Val Leu Gly Ala Ala Ala Thr Thr Thr Gly Gly Gly Thr Gln Leu Thr Val Leu Gly Ala Ala Ala Thr Thr Thr 260 265 270 260 265 270

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Page 168 Page 168

SequenceListing (3).txt SequenceListing (3) . txt 405 410 415 405 410 415

<210> 202 <210> 202 <211> 339 <211> 339 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

<400> 202 <400> 202 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggagggtc cctgagactc 60 gaggtgcagc tggtggagtc tgggggaggo ttggtacago ctggagggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatggca tgagctgggt ccgccaggct 120 tcctgtgcag cctctggatt caccttcagt agctatggca tgagctgggt ccgccaggct 120

ccaagacaag ggcttgagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180 ccaagacaag ggcttgagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180

gcggactcag tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 gcggactcag tgaagggccg attcaccato tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acagccacgt attactgtgc gaaagaaaat 300 ctgcaaatga acagcctgag agccgaggac acagccacgt attactgtgo gaaagaaaat 300

gtggactggg gccagggcac cctggtcacc gtctcctca 339 gtggactggg gccagggcad cctggtcacc gtctcctca 339

<210> 203 <210> 203 <211> 113 <211> 113

Page 169 Page 169

SequenceListing (3).txt SequenceListing (3) . txt <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 203 <400> 203 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Arg Gln Gly Leu Glu Trp Val Gly Met Ser Trp Val Arg Gln Ala Pro Arg Gln Gly Leu Glu Trp Val 35 40 45 35 40 45

Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Ala Asp Ser Val Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Ala Asp Ser Val 50 55 60 50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 85 90 95

Ala Lys Glu Asn Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Lys Glu Asn Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 100 105 110

Ser Ser

<210> 204 <210> 204 <211> 1083 <211> 1083 <212> DNA <212> DNA <213> Artificial Sequence <213> Artificial Sequence

Page 170 Page 170

SequenceListing (3).txt

<400> 204 atgctgctgc tggtgaccag cctgctgctg tgcgaactgc cgcatccggc gtttctgctg 60

attccggagg tgcagctggt ggagtctggg ggaggcttgg tacagcctgg agggtccctg 120

agactctcct gtgcagcctc tggattcacc ttcagtagct atggcatgag ctgggtccgc 180

caggctccaa gacaagggct tgagtgggtg gccaacataa agcaagatgg aagtgagaaa 240

tactatgcgg actcagtgaa gggccgattc accatctcca gagacaattc caagaacacg 300

ctgtatctgc aaatgaacag cctgagagcc gaggacacag ccacgtatta ctgtgcgaaa 360

gaaaatgtgg actggggcca gggcaccctg gtcaccgtct cctcagcggc cgcaactacc 420

acccctgccc ctcggccgcc gactccggcc ccaaccatcg caagccaacc cctctccttg 480

cgccccgaag cttgccgccc ggccgcgggt ggagccgtgc atacccgggg gctggacttt 540

gcctgcgata tctacatttg ggccccgctg gccggcactt gcggcgtgct cctgctgtcg 600

ctggtcatca ccctttactg caagaggggc cggaagaagc tgctttacat cttcaagcag 660

ccgttcatgc ggcccgtgca gacgactcag gaagaggacg gatgctcgtg cagattccct 720

gaggaggaag aggggggatg cgaactgcgc gtcaagttct cacggtccgc cgacgccccc 780

gcatatcaac agggccagaa tcagctctac aacgagctga acctgggaag gagagaggag 840

tacgacgtgc tggacaagcg acgcggacgc gacccggaga tgggggggaa accacggcgg 900

aaaaaccctc aggaaggact gtacaacgaa ctccagaaag acaagatggc ggaagcctac 960

tcagaaatcg ggatgaaggg agagcggagg aggggaaagg gtcacgacgg gctgtaccag 1020

ggactgagca ccgccactaa ggatacctac gatgccttgc atatgcaagc actcccaccc 1080

cgg 1083

<210> 205 <211> 361 <212> PRT <213> Artificial Sequence

<220> <223> Description of Artificial Sequence: Synthetic Page 171

SequenceListing (3).txt SequenceListing (3) txt polypeptide polypeptide

<400> 205 <400> 205 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 1 5 10 15

Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 20 25 30

Phe Thr Phe Ser Ser Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Arg Phe Thr Phe Ser Ser Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Arg 50 55 60 50 55 60

Gln Gly Leu Glu Trp Val Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Gln Gly Leu Glu Trp Val Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys 65 70 75 80 70 75 80

Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 85 90 95

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Lys Glu Asn Val Asp Trp Gly Gln Gly Thr Ala Thr Tyr Tyr Cys Ala Lys Glu Asn Val Asp Trp Gly Gln Gly 115 120 125 115 120 125

Thr Leu Val Thr Val Ser Ser Ala Ala Ala Thr Thr Thr Pro Ala Pro Thr Leu Val Thr Val Ser Ser Ala Ala Ala Thr Thr Thr Pro Ala Pro 130 135 140 130 135 140

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 145 150 155 160 145 150 155 160

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 165 170 175 165 170 175

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Page 172 Page 172

SequenceListing (3).txt SequenceListing (3) . txt 180 185 190 180 185 190

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys 195 200 205 195 200 205

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 210 215 220 210 215 220

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 225 230 235 240 225 230 235 240

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 245 250 255 245 250 255

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 260 265 270 260 265 270

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 275 280 285 275 280 285

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 290 295 300 290 295 300

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 305 310 315 320 305 310 315 320

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 325 330 335 325 330 335

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 340 345 350 340 345 350

Leu His Met Gln Ala Leu Pro Pro Arg Leu His Met Gln Ala Leu Pro Pro Arg 355 360 355 360

<210> 206 <210> 206

Page 173 Page 173

SequenceListing (3).txt SequenceListing (3) txt <211> 4 <211> 4 <212> PRT <212> PRT <213> Artificial Sequence <213> Artificial Sequence

<400> 206 <400> 206 Gly Phe Leu Gly Gly Phe Leu Gly 1 1

Page 174 Page 174

Claims

CLAIMS 02 Jun 2025 2018352245 02 Jun 2025 CLAIMS WHAT WHAT ISISCLAIMED CLAIMEDIS:IS:

1. 1. A chimeric A chimeric antigen antigen receptor receptor (CAR), (CAR), comprising comprising at least at least oneone extracellular extracellular

antigen binding antigen bindingdomain domain comprising comprising a CD22 a CD22 antigen antigen binding binding domain domain comprising comprising an an aminoacid acidsequence sequenceofofanyany oneone of of SEQSEQ ID NOs: 52,72, 62,82, 72,92, 82,102, 92, 112, 102, 122, 112, 122, 2018352245

amino ID NOs: 52, 62,

132, 152, or 132, 152, or 162, 162, atat least least one one linker linker or or spacer spacer domain, domain,atatleast leastone onetransmembrane transmembrane domain, and at least one intracellular signaling domain. domain, and at least one intracellular signaling domain.

2. TheThe 2. CAR CAR of claim of claim 1, wherein 1, wherein the atthe at least least one one transmembrane transmembrane domaindomain comprises comprises

a transmembrane a domain transmembrane domain of the of the alpha, alpha, beta beta or or zeta zeta chain chain of of a proteinselected a protein selectedfrom from a a T-cell receptor, T-cell receptor, aa CD8, CD8, aaCD28, CD28, a CD3 a CD3 epsilon, epsilon, a CD45, a CD45, a CD4,a aCD4, CD5, aa CD5, CD8, aa CD8, a CD9, aa CD16, CD9, CD16,a aCD22, CD22,a aCD33, CD33, a CD37, a CD37, a CD64, a CD64, a CD80, a CD80, a CD86, a CD86, a CD134, a CD134, a a CD137and CD137 andaa CD154. CD154.

3. TheThe 3. CARCAR of claim of claim 1 or1 2, or wherein 2, wherein thethe CD22 CD22 antigen antigen binding binding domain, domain, thethe at at

least least one intracellular signaling one intracellular signaling domain, orboth domain, or bothare areconnected connected to to thethe at least at least oneone

transmembrane transmembrane domain domain by abylinker a linker or or spacer spacer domain. domain.

4. TheThe 4. CAR CAR of anyofone anyofone of claims claims 1 to 3,1 wherein to 3, wherein the at the at least least one linker one linker or spacer or spacer

domainisis derived domain derivedfrom fromthe theextracellular extracellular domain ofCD8 domain of CD8or or CD28, CD28, and and is linked is linked to to thethe

at least at leastone onetransmembrane domain. transmembrane domain.

5. 5. TheThe CARCAR of one of any any of oneclaims of claims 1 to 14,towherein 4, wherein the CD22 the CD22 antigen antigen binding binding

domainisis preceded domain precededbybya aleader leaderpeptide. peptide.

6. TheThe 6. CAR CAR of anyof any one of one of 1claims claims to 5, 1 to 5, the wherein wherein the one at least at least one intracellular intracellular

signaling domain signaling further comprises domain further comprisesa aCD3 CD3 zeta zeta intracellulardomain. intracellular domain.

7. 7. TheThe CAR CAR of anyof any one of one of 1claims claims to 6, 1 to 6, the wherein wherein the one at least at least one intracellular intracellular

signaling signaling domain comprises domain comprises a costimulatory a costimulatory domain, domain, a primary a primary signaling signaling domain, domain, or or any combination any combinationthereof. thereof.

135 135

21769856_1(GHMatters) 21769856_1 (GHMatters)P113421.AU P113421.AU 02/06/2025 02/06/2025

8. TheThe CAR CAR of claim 7, wherein the costimulatory domain domain comprises a signaling 02 Jun 2025 2018352245 02 Jun 2025

8. of claim 7, wherein the costimulatory comprises a signaling

domain of domain of OX40, CD70,CD27, OX40, CD70, CD27,CD28, CD28, CD5, CD5, ICAM-1, ICAM-1, LFA-1 LFA-1 (CD11a/CD18), (CD11a/CD18), ICOS ICOS (CD278), (CD278), DAP10, DAP12,oror4-1BB DAP10, DAP12, 4-1BB(CD137). (CD137).

9. An An 9. isolated isolated nucleic nucleic acid, acid, optionally optionally a vector, a vector, encoding encoding the the CAR CAR of anyofone anyofone of claims claims 1 1toto8.8. 2018352245

10. Theisolated 10. The isolated nucleic nucleic acid acid molecule molecule ofofclaim claim9,9,wherein whereinthethenucleic nucleicacid acid moleculeisis operably molecule operably linked linked to to an an expression control sequence. expression control sequence.

11. 11. The The isolatednucleic isolated nucleic acid acid molecule molecule of claim of claim 9 or9 10, or 10, wherein wherein the extracellular the extracellular

CD22 antigenbinding CD22 antigen binding domain domain is encoded is encoded by any by any one one of ID of SEQ SEQ ID51, NOs: NOs: 61,51, 71,61, 81,71, 81,

91, 101,111, 91, 101, 111,121, 121, 131, 131, 151, 151, or 161. or 161.

12. 12. A A population population of of T cells,comprising T cells, comprising thethe CARCAR of any of any oneclaims one of of claims 1 to 1 8 to or 8the or the isolated isolated nucleic nucleic acid acid molecule of any molecule of any one oneof of claims claims99toto 11, 11, optionally optionally wherein whereinthe theTT cells cells are T cells are T cells ofofaasubject subjecthaving having a hematological a hematological cancer. cancer.

13. 13. A A pharmaceutical pharmaceutical composition composition comprising comprising an anti-tumor an anti-tumor effective effective amount amount of of the population of T cells of claim 12. the population of T cells of claim 12.

14. 14. A Amethod method of treating of treating a hematological a hematological cancer cancer in ainsubject, a subject, the the method method

comprisingadministering comprising administering to to the the subject subject an anti-tumor an anti-tumor effective effective amount amount of the of the population ofof TTcells population cellsofofclaim claim1212 or or thethe pharmaceutical pharmaceutical composition composition of claim of claim 13, 13, wherein the wherein the TTcells cells are are TTcells cells of of the the subject, subject, wherein wherein the the CAR CAR targetsthethe targets

hematologicalcancer. hematological cancer.

15. 15. Use Use of of thethe isolatednucleic isolated nucleic acid acid molecule molecule of any of any one one of claims of claims 9 to 9 11toor11 or the the population of population of TTcells cells of of claim claim 12 12ininthe the manufacture manufactureofofa amedicament medicament for for treating treating a a hematologicalcancer hematological cancerinina subject, a subject,wherein wherein the the T cells T cells are are T cells T cells of subject, of the the subject, whereinthe wherein the CAR CAR targetsthe targets thehematological hematological cancer. cancer.

16. 16. The The method method of claim of claim 14 use 14 or or use of claim of claim 15, 15, wherein wherein the the hematological hematological cancer cancer is is leukemia, lymphoma, leukemia, lymphoma, or or multiple multiple myeloma. myeloma.

136 136

17. The method or use of claim 16, wherein the leukemia is chronic lymphocytic 02 Jun 2025 02 Jun 2025

17. The method or use of claim 16, wherein the leukemia is chronic lymphocytic

leukemia (CLL), leukemia (CLL), acute acutelymphocytic lymphocyticleukemia leukemia (ALL), (ALL), or chronic or chronic myelogenous myelogenous

leukemia leukemia (CML). (CML).

18. Themethod 18. The method or or use use of claim of claim 16, wherein 16, wherein the lymphoma the lymphoma is mantle is mantle cell cell lymphoma, non-Hodgkin’slumphoma lymphoma, non-Hodgkin's lumphoma(NHL) (NHL) or or Hodgkin’slymphoma. Hodgkin's lymphoma. 2018352245

2018352245

137 137

CD22 Targeting CD8 CD137 CD3C Domain

FIGURE 1

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2/28 2/28

LTG2202: LP-16P-CD8TM-41BB-CD3zeta LP-16P-CD8 TM-41BB-CD3zetanucleic nucleicacid acidsequence sequence(SEQ (SEQID IDNO: NO:3) 3)

GCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGG ITCCTCCTGATCCCACAAGTACAACTCCAGCAAAGCGGGCCTGGTCTGG GAAGCCGTCACAGACGCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGT GAAGCCGTCACAGACGCTTTCACTTACGTGTGCGATCTCCGGTGACTCCGT GAGTTCTAATAGCGCGGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAG GAGTTCTAATAGCGCGGCTTGGAACTGGATTAGGCAGTCTCCATCCCGAG GATTGGAATGGCTCGGCAGGACTTATTATAGAAGTAAGTGGTACAACGAT GATTGGAATGGCTCGGCAGGACTTATTATAGAAGTAAGTGGTACAACGAT TATGCAGTCTCTGTGAAATCTCGCATCACCATTAACCCAGACACGTCTAAG TATGCAGTCTCTGTGAAATCTCGCATCACCATIAACCCAGACACGTCTAAG AATCAGTTCAGTCTTCAACTCAACTCTGTAACCCCCGAAGATACAGCGGT AATCAGTTCAGTCTTCAACTCAACTCTGTAACCCCCGAAGATACAGCGGT CTACTACTGTGCTCAGGAGGTGCAACCCCACGATGCTTTTGATATCTGGGG CCAGGGTACCATGGTTACGGTGTCTTCTGGGGGAGGGGGGTCCGGTGGGG GAGGATCAGGGGGTGGGGGCAGCGACATACAAATGACGCAATCCCCGTC TTCTGTTTCTGCGTCTGTCGGAGATAAAGTAACAATAACCTGTCGAGCGTC ITCTGTTTCTGCGTCTGTCGGAGATAAAGTAACAATAACCTGTCGAGCGTC ACAGGACGTTAGTGGCTGGCTTGCGTGGTATCAGCAAAAACCGGGGCTCG ACAGGACGTTAGTGGCTGGCTTGCGTGGTATCAGCAAAAACCGGGGCTCG CCCCGCAATTGCTTATATTTGGAGCGAGTACTCTTCAGGGCGAGGTACCTA CCCCGCAATTGCTTATATTTGGAGCGAGTACTCTTCAGGGCGAGGTACCTA GCAGATTTTCTGGGTCCGGCTCAGGTACGGACTTCACCCTGACCATATCTA GCTTGCAGCCTGAAGATTTCGCCACCTACTATTGTCAACAGGCGAAGAAC GCTTGCAGCCTGAAGATTTCGCCACCTACTATTGTCAACAGGCGAAGAAC TTTCCATATACGTTCGGGCAGGGTACGAAATTGGAGATAAAAGCGGCCGC ITTCCATATACGTTCGGGCAGGGTACGAAATTGGAGATAAAAGCGGCCGC AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGG GCCGTGCATACCCGGGGGCTGGACTITGCCTGCGATATCTACATTTGGGCC GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTI TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG FTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACO GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACO CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG LTG2202: LP-16P-CD8 TM-41BB-CD3zet TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:4) 4)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL PLNSVTPEDTAVYYCAQEVQPHDAFDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVQPHDAFDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQ GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR

FIGURE 2A

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3/28 3/28

LTG2246: LP-24P-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 13)

TGCTGTTGGTGACATCACTTCTGCTCTGTGAACTCCCCCATCCAGCO ATGCTGCTGTTGGTGACATCACTTCTGCTCTGTGAACTCCCCCATCCAGCC TTTCTGCTTATACCGCAAGTACAGCTGCAACAATCTGGCCCTGGGCTTGTC AAACCCTCTCAGACTTTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGT] AAACCCTCTCAGACTTTGTCCTTGACGTGCGCGATAAGTGGCGATTCAGTT AGTTCTAACAGCGCCGCTTGGAACTGGATTAGACAGAGCCCCAGTCGGGG ACTCGAATGGCTTGGCCGGACTTATTATCGCAGTAAATGGTATAATGATTA ACTCGAATGGCTTGGCCGGACTTATTATCGCAGTAAATGGTATAATGATTA TGCTGTGAGTGTGAAAAGTAGGATCACAATCAACCCCGATACGAGCAAGA FGCTGTGAGTGTGAAAAGTAGGATCACAATCAACCCCGATACGAGCAAGA ATCAATTCTCATTGCAACTGAACAGCGTCACTCCCGAGGATACAGCTGTA CATTATTGTGCAAGAGAAGGTGGGTGGTATGGCGAGATGGATGTATGGG ATTATTGTGCAAGAGAAGGTGGGTGGTATGGCGAGATGGATGTATGGGG GAAAGGAACTACGGTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTG GAAAGGAACTACGGTAACTGTGTCCAGTGGCGGAGGCGGTTCAGGTGGTG GAGGCTCTGGAGGAGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGCT GAGGCTCTGGAGGAGGAGGGTCCGAAATCGTGCTTACCCAGTCTCCGGC ACTCTGAGCGTTAGTCCGGGTGAAAGGGCCTCACTCTCTTGTCGAGCTTCA ACTCTGAGCGTTAGTCCGGGTGAAAGGGCCTCACTCTCTIGTCGAGCTICA CAGTCAGTCTCTTCCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGGC CAGTCAGTCTCTTCCTACTTGGCTTGGTATCAGCAGAAGCCAGGTCAGGC GCCCCGCTTGCTCATTTACGACGCAAGCACACGAGCGACAGGCATTCCAG ACAGATTTTCTGGTTCTGGTTCTGGCACGGACTTTACTCTTACTATAAACT ACAGATTTTCTGGTTCTGGTTCTGGCACGGACTTTACTCTTACTATAAACI ACTTGAGGCAGAGGATGCTGCGACTTACTATTGTCACCAATCAAGCTC CACTTGAGGCAGAGGATGCTGCGACTTACTATTGTCACCAATCAAGCTCT CTGCCTTACACCTTTGGGCAAGGCACCAAACTCGAAATCAAGGTTACGGT CTGCCTTACACCTTTGGGCAAGGCACCAAACTCGAAATCAAGGTTACGG ATCATCTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGG ATCATCTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGC CCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCC CCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCC CGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGAT CGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGAT ATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCG ATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCG CTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACAT CTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACAT CTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG CTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCG ACGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAC CGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGA ATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGT ATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGT GCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGG GCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGC CGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGA CGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGA TGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGG TGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGG AAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGAT AAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGA CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG ACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG LTG2246: LP-24P-CD8 TM-41BB-CD3 zeta amino acid sequence (SEQ ID NO: 14)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAREGGWYGEMDVWGKGTTVTVSSGGGGSGGGGS QLNSVTPEDTAVYYCAREGGWYGEMDVWGKGTTVTVSSGGGGSGGGGSG GGGSEIVLTQSPATLSVSPGERASLSCRASQSVSSYLAWYQQKPGQAPRLLIY GGGSEIVLTQSPATLSVSPGERASLSCRASQSVSSYLAWYQQKPGQAPRLLIY DASTRATGIPDRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPYTFGQGTH LEIKVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF LEIKVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLD KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALHMQALPPR DGLYQGLSTATKDTYDALHMQALPPR

FIGURE 2B SUBSTITUTE SHEET (RULE 26)

LTG2247: LP-25P-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 23)

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGC ATGCTICTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGTT FTCCTCCTGATCCCACAAGTACAGCTCCAACAGAGTGGACCTGGTCTCGT AAGCCGTCCCAAACACTGTCTTTGACGTGCGCTATTAGTGGCGACAGCG2 AAGCCGTCCCAAACACTGTCTTTGACGTGCGCTATTAGTGGCGACAGCGI ATCATCCAATTCTGCTGCTTGGAACTGGATTAGACAGTCACCGTCCAGAG ATCATCCAATTCTGCTGCTTGGAACTGGATTAGACAGTCACCGTCCAGAG GCTTGGAATGGCTGGGCAGGACGTACTACCGCTCAAAATGGTATAACGAT GCTTGGAATGGCTGGGCAGGACGTACTACCGCTCAAAATGGTATAACGA7 FACGCGGTTAGTGTCAAATCCAGGATTACCATTAACCCTGACACAAGTA TACGCGGTTAGTGTCAAATCCAGGATTACCATTAACCCTGACACAAGTAA GAATCAGTTITCTCTTCAGCTGAATTCCCTGACTCCTGAGGATACGGCCGT GAATCAGTTTTCTCTTCAGCTGAATTCCCTGACTCCTGAGGATACGGCCGT TTACTACTGTGCCCGAGAACACCAGAATGAGGCGGCTTTTGATATTTGGG ITACTACTGTGCCCGAGAACACCAGAATGAGGCGGCTTTTGATATTTGGG GGCAAGGAACAATGGTCACAGTTAGCAGTGGGGGGGGTGGCTCCGGGG6 GGCAAGGAACAATGGTCACAGTTAGCAGTGGGGGGGGTGGCTCCGGGGG AGGTGGTTCCGGCGGCGGTGGTTCTCAATCCGTCCTGACACAACCTCCCTO AGGTGGTTCCGGCGGCGGTGGTTCTCAATCCGTCCTGACACAACCTCCCTC AGCGAGCGGGACTCCCGGTCAAAGGGTGACCATCTCTTGTTCTGGGGGAC AGCGAGCGGGACTCCCGGTCAAAGGGTGACCATCTCTTGTTCTGGGGGAC GTAGTAACATCGGGACAAATACTGCGTCCTGGTATCAGCAACTCCCTGGG GTAGTAACATCGGGACAAATACTGCGTCCTGGTATCAGCAACTCCCTGGG ACCGCTCCCAAGTTGTTGATATATCGCAATACGCAACGACCTAGTGGGAT ACCGCTCCCAAGTTGTTGATATATCGCAATACGCAACGACCTAGTGGGAI ACCTGATAGATTCAGCGGAAGCAAAAGTGGTACGAGTGCGTCTTTGGCAA TATCTGGCCTCCAGTCCGAGGACGAAGCGGATTACTATTGTGCGGCCTGG FATCTGGCCTCCAGTCCGAGGACGAAGCGGATTACTATTGTGCGGCCTGG GATGACTCACTGAATGGTTATGTGTTCGGTGCAGGTACTCAACTCACCGTA CTTGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGC CTTGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGC CCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCC GGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGAT TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGC TCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGC TGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATC TGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATC TTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG TTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGG ATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGG ATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGC GTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAA GTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGA ICAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTC TCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTG CTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGC GGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGAT GGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGA GGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGG0 GGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGA AAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA AGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATA CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG CCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG LTG2247: LP-25P-CD8TM-41BB-CD3zeta LP-25P-CD8 TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:24) 24)

ALLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAW MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAW NWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSLTPED NWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSLTPE TAVYYCAREHQNEAAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSAS TAVYYCAREHQNEAAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSAS GTPGQRVTISCSGGGSNIGTNTASWYQQLPGTAPKLLIYRNTQRPSGIPDRFSGSKSGT GTPGQRVTISCSGGGSNIGTNTASWYQQLPGTAPKLLIYRNTQRPSGIPDRFSGSKSG ASLAISGLQSEDEADYYCAAWDDSLNGYVFGAGTQLTVLGAAATTTPAPRPPTPAP SASLAISGLQSEDEADYYCAAWDDSLNGYVFGAGTQLTVLGAAATTTPAPRPPTPAP TIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKE TIASQPLSLRPEACRPAAGGAVHTRGLDFACDIVIWAPLAGTCGVLLLSLVITLYCKR GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGO GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQ JQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

FIGURE 2C FIGURE 2C

SUBSTITUTE SHEET (RULE 26)

LTG2248: LP-11s-CD8 TM-41BB-CD3zetanucleic TM-41BB-CD3zeta nucleicacid acidsequence sequence(SEQ (SEQID IDNO: NO:33) 33)

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGT FTCCTCCTGATCCCACAAGTCCAGTTGCAACAGTCCGGGCCAGGTCTGGT AAGCCATCCCAAACTCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGT AAGCCATCCCAAACTCTGAGTTTGACGTGCGCTATTAGCGGAGATTCCGT GTCCAGCAATTCTGCAACCTGGAATTGGATCCGGCAGAGTCCGAGTGGCG GTCCAGCAATTCTGCAACCTGGAATTGGATCCGGCAGAGTCCGAGTGGCC GTTTGGAATGGCTCGGACGCACTTACTACAGGAGCAAATGGTACGATGAT GTTTGGAATGGCTCGGACGCACTTACTACAGGAGCAAATGGTACGATGA TATGCTGTTTCTGTGCGCTCTCGAATCACCATGAATCCTGATACTTCTAAG FATGCTGTTTCTGTGCGCTCTCGAATCACCATGAATCCIGATACTTCTAAG AACCAATTTTCTTTGCAGTTGAACTCCGTCACGCCTGAAGATACTGCGGTO AACCAATTTTCTTTGCAGTTGAACTCCGTCACGCCTGAAGATACTGCGGTC TACTATTGCGCACGCGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCA TACTATTGCGCACGCGAAGGCGTAGCCGGCGATTTTGATTACTGGGGGCA AGGAACATTGGTCACGGTCTCCTCTGGTGGAGGAGGATCAGGAGGCGGG AGGAACATTGGTCACGGTCTCCTCTGGTGGAGGAGGATCAGGAGGCGGG GGTTCAGGTGGAGGTGGGAGCGATATTCAACTTACGCAGTCTCCGAGCAG TCTTTCTGCTTCCGTGGGAGACCGAGTGACGATTACTTGTAGGGCATCTCA ICTTTCTGCTTCCGTGGGAGACCGAGTGACGATTACTTGTAGGGCATCTC GTCAATAAGTTCCTATCTTAACTGGTATCAGCAGAAGCCTGGAAAGGCTC GTCAATAAGTTCCTATCTTAACTGGTATCAGCAGAAGCCTGGAAAGGCTC CAAAACTTCTTATTTATGCCGCATCCTCATTGCAATCCGGCGTGCCTTCCC GATTTTCCGGATCTGGCTCAGGCACTGACTTTACCTTGACTATTAGTTCO GATTTTCCGGATCTGGCTCAGGCACTGACTTTACCTTGACTATTAGTTCCC TTCAACCAGAAGATTTTGCTACCTATTACTGCCAACAATCATACAGTACCO ITCAACCAGAAGATTTTGCTACCTATTACTGCCAACAATCATACAGTACCC CATATACATTCGGCCAAGGCACGAAATTGGAGATTAAAGCGGCCGCAACT ACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC. ACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCA ACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGGCGGGTGGAGCCG ACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCO TGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGC FGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGC TGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACT GCAAGAGGGGCCGGAAGAAGCTGCTTITACATCTTCAAGCAGCCGTTCATO GCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATG CGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCC CGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCC TGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCC TGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCC GCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCT GCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCT GAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGA CGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAG GACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGA GACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGA AATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCT GTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATA GTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATA TGCAAGCACTCCCACCCCGG TGCAAGCACTCCCACCCCGG LTG2248: LP-11s-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO : 34)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSATW MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSATW NWIRQSPSGGLEWLGRTYYRSKWYDDYAVSVRSRITMNPDTSKNQFSLQLNSVTP NWIRQSPSGGLEWLGRTYYRSKWYDDYAVSVRSRITMNPDTSKNQFSLQLNSVTPE DTAVYYCAREGVAGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSS DTAVYYCAREGVAGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLS ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIKAAATTTPAPRPPTPAPTIASQPI SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLI SLRPEACRPAAGGAVHTRGLDFACDIVIWAPLAGTCGVLLLSLVITLYCKRGRKKLL IFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYT YIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNE LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKG LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKG ERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR ERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

FIGURE 2D

SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

6/28 6/28

LTG2249: LP-12S-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 43)

ATGCTTCTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA ATGCTICTCCTGGTGACAAGCCTTCTGCTCTGTGAGTTACCACACCCAGCA TTCCTCCTGATCCCACAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTTGT FTCCTCCTGATCCCACAAGTTCAGTTGCAGCAGAGTGGCCCTGGGCTIGTT AAACCATCACAGACGCTCTCACTGACCTGTGCCATCTCTGGAGACAGTGT AAACCATCACAGACGCTCTCACTGACCTGTGCCATCTCTGGAGACAGTG AAGTTCTAACTCAGCCGCGTGGAATTGGATTAGACAATCACCAAGCCGGG AAGTTCTAACTCAGCCGCGTGGAATTGGATTAGACAATCACCAAGCCGGG GACTTGAATGGCTTGGTCGGACGTACTATAGATCTAAGTGGTATAATGAC TACGCAGTGTCAGTGAAATCACGGATAACCATAAACCCTGACACCAGCAA FACGCAGTGTCAGTGAAATCACGGATAACCATAAACCCTGACACCAGCAA AAACCAATTTTCTCTTCAGCTTAATTCCGTCACGCCAGAAGATACGGCCG AAACCAATTTTCTCTTCAGCTTAATTCCGTCACGCCAGAAGATACGGCCGT TTACTACTGTGCGAGGGAAGGTGATGACGCATTGGACATCTGGGGTCAGG FTACTACTGTGCGAGGGAAGGTGATGACGCATTGGACATCTGGGGTCAGG GGACCATGGTGACTGTCTCTTCCGGCGGGGGGGGTAGTGGAGGGGGTGGC GGACCATGGTGACTGTCTCTTCCGGCGGGGGGGGTAGTGGAGGGGGTGGG TCAGGTGGTGGCGGGTCAGATATACAAATGACACAGAGCCCTAGTAGTCT TCAGGTGGTGGCGGGTCAGATATACAAATGACACAGAGCCCTAGTAGTC GAGTGCTTCAGTGGGCGACCGCGTAACTATAACCTGTAGAGCATCCCA GAGTGCTTCAGTGGGCGACCGCGTAACTATAACCTGTAGAGCATCCCAAA CATTTCCCACTTCCTTAATTGGTACCAGCAGAAGCCGGGCACAGCGCC GCATTTCCCACTTCCTTAATTGGTACCAGCAGAAGCCGGGCACAGCGCC AAACTCCTGATCACCACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCCG AAACTCCTGATCACCACTGCGAGCGGACTTGGTTCAGGTGTTCCTAGCC ATTTAGTGGGTCAGGTAGCGGTACAGATTTCACTCTCACGATAAACTCCCT GTTTAGTGGGTCAGGTAGCGGTACAGATTTCACTCTCACGATAAACTCCCI TCAGCCTGAGGACCTGGCGACATATTACTGTCAACAATCCTATACCACCC TCAGCCTGAGGACCTGGCGACATATTACTGTCAACAATCCTATACCACCA CACTGACATTCGGAGGGGGCACAAAACTGGAGATCAAAGCGGCCGCAAC TACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC TACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCC AACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCC GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG GTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCC CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTAC TGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCAT TGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCAT GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCC GCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCC TGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGG) CTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTC CGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGC CGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGC TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGG TGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGG ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAG AAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGC AAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGC TGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCAT TGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATOCCTTGCA ATGCAAGCACTCCCACCCCGG ATGCAAGCACTCCCACCCCGG LTG2249: LP-12S-CD8TM-41BB-CD3zeta LP-12S-CD8 TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:44) 44)

LLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQF SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAREGDDALDIWGQGTMVTVSSGGGGSGGGGSGGGG QLNSVTPEDTAVYYCAREGDDALDIWGQGTMVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQSISHFLNWYQQKPGTAPKLLITTASG SDIQMTQSPSSLSASVGDRVTITCRASQSISHFLNWYQQKPGTAPKLLITTASG LGSGVPSRFSGSGSGTDFTLTINSLQPEDLATYYCQQSYTTPLTFGGGTKLEL LGSGVPSRFSGSGSGTDFTLTINSLQPEDLATYYCQQSYTTPLTFGGGTKLEIK AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAP AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAP LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPER LAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE EEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS TATKDTYDALHMQALPPR

FIGURE 2E

SUBSTITUTE SHEET (RULE 26)

LTG2203: LP-16P3-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 53)

ATGTTGTTGCTTGTCACAAGCCTTCTTCTCTGTGAGCTTCCGCACCCGGCTTTCCT ATGTTGTTGCTTGTCACAAGCCTTCTTCTCTGTGAGCTTCCGCACCCGGCTTTCCT GCTGATCCCGCAGATACAGCTTCAGCAGTCCGGCCCCGGTCTGGTAAAGCCGTC GCTGATCCCGCAGATACAGCTTCAGCAGTCCGGCCCCGGTCTGGTAAAGCCGTCC CAAACGCTTTCACTCACATGCGCGATCTCTGGTGATTCTGTGTCATCCAACAGC CAAACGCTTTCACTCACATGCGCGATCTCTGGTGATTCTGTGTCATCCAACAGCG CAGCATGGAATTGGATCCGCCAATCACCCAGTAGAGGCTTGGAGTGGTTGGGCC CAGCATGGAATTGGATCCGCCAATCACCCAGTAGAGGCTTGGAGTGGTTGGGCC GGACTTATTATCGAAGTAAGTGGTACAATGATTATGCAGTCTCAGTTAAATCCA GGACTTATTATCGAAGTAAGTGGTACAATGATTATGCAGTCTCAGTTAAATCCAG GATCACTATTAACCCAGATACAAGTAAAAACCAGTTCTCATTGCAACTTAATTCO ATCACTATTAACCCAGATACAAGTAAAAACCAGTTCTCATTGCAACTTAATTCO GTAACTCCGGAGGACACTGCAGTATATTACTGCGCTCAGGAGGTGCAGCCTGAT GATGCTCTGGACATTTGGGGACAAGGCACGATGGTCACGGTTAGTTCCGGGGG6 GATGCTCTGGACATTTGGGGACAAGGCACGATGGTCACGGTTAGTTCCGGGGGG GGAGGTTCTGGCGGAGGTGGTAGTGGGGGGGGCGGCAGTGACATCCAGATGACA GGAGGTTCTGGCGGAGGTGGTAGTGGGGGGGGCGGCAGTGACATCCAGATGACA CAGAGTCCCAGCAGCGTGTCTGCGTCAGTCGGGGATAAGGTAACAATTACGTGT AGAGCGAGCCAGGACGTTTCCGGGTGGCTGGCGTGGTACCAACAAAAACCCGGT CTCGCTCCGCAGTTGCTCATCTCTGGAGCGTCCACCCTTCAGGGAGAGGTGCCTA CTCGCTCCGCAGTTGCTCATCTCTGGAGCGTCCACCCTTCAGGGAGAGGTGCCTA GCAGATTTTCTGGGTCTGGATCCGGCACGGATTTTACACTTACGATTTCCTCTCTT GCAGATTTTCTGGGTCTGGATCCGGCACGGATTTTACACTTACGATTICCTCTCTT CAACCCGAAGATTTTGCTACTTACTATTGCCAGCAGGCCAAAAACTTCCCGTACA CAACCCGAAGATTTTGCTACTTACTATTGCCAGCAGGCCAAAAACTTCCCGTACA CGTTTGGACAGGGCACAAAGTTGGAAATTAAGGCGGCCGCAACTACCACCCT CGTTTGGACAGGGCACAAAGTTGGAAATTAAGGCGGCCGCAACTACCACCCCTG CCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCC CCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCG CCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTG CCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGA CTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCT CTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTC CTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTT CATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGAC ACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACG GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCA GATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCA AGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCT AGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTA CAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGA. GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAA GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATO GGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATC GGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGG GGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGG ACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCA CCCCGG CCCCGG LTG2203: LTG2203:LP-16P3-CD8 LP-16P3-CD8STM-41BB-CD3zeta amino TM-41BB-CD3zeta acid acid amino sequence (SEQ ID sequence NO: ID (SEQ 54) NO: 54)

MLLLVTSLLLCELPHPAFLLIPQIQLQQSGPGLVKPSQTLSLTCAISGDSVSSNS AAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSV PEDTAVYYCAQEVQPDDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQS TPEDTAVYYCAQEVQPDDALDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQS VSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFS PSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISGASTLQGEVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIKAAATTTPAPRPPTPAR SGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTKLEIKAAATTTPAPRPPTPAP TIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCK TIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKR GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQ GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQ QLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYS EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR EIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

FIGURE 2F

SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

8/28 8/28

LTG2204: LP-16P16-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 63)

ATGCTGCTTTTGGTAACTTCCCTCCTTTTGTGCGAGCTGCCCCATCCAGCG ATGCTGCTTTTGGTAACTTCCCTCCTTTTGTGCGAGCTGCCCCATCCAGCG TTCCTCCTCATCCCTCAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGT FTCCTCCTCATCCCTCAAGTACAGTTGCAGCAGTCAGGACCTGGCCTTGTC AAACCATCCCAAACTCTCAGCCTCACGTGTGCTATTTCTGGTGACTCAGTA AGTAGCAATAGCGCTGCTTGGAACTGGATCAGACAATCTCCCTCCAGGGC AGTAGCAATAGCGCTGCTTGGAACTGGATCAGACAATCTCCCTCCAGGGG TCTCGAATGGCTGGGGCGAACCTATTACCGATCTAAATGGTATAACGATT TCTCGAATGGCTGGGGCGAACCTATTACCGATCIAAATGGTATAACGATT ATGCAGTATCCGTGAAATCCAGGATTACAATCAACCCAGATACGTTCAAG ATGCAGTATCCGTGAAATCCAGGATTACAATCAACCCAGATACGTICAA AATCAATTCTCTCTTCAGCTCAACTCCGTAACTCCAGAGGACACTGCGGT. AATCAATTCTCTCTTCAGCTCAACTCCGTAACTCCAGAGGACACTGCGGTA TATTATTGCGCCCAAGAAGTCGAGCCACACGATGCCCTCGATATCTGGGC TCAAGGTACCATGGTTACAGTTAGTAGTGGGGGTGGGGGAAGCGGGGGC GGTGGGTCCGGTGGCGGGGGTTCAGACATCAAGATGACCCAATCCCCAAG GGTGGGTCCGGTGGCGGGGGTTCAGACATCAAGATGACCCAATCCCCAAG CTCTGTTTCAGCATCCGTGGGCGATAAGGTAACCATTACATGCAGAGCGA CTCTGTTTCAGCATCCGTGGGCGATAAGGTAACCATTACATGCAGAGCGA GTCAGGACGTTTCAGGGTGGCTGGCTTGGTACCAGCAAAAACCGGGACTC GTCAGGACGTTTCAGGGTGGCTGGCTTGGTACCAGCAAAAACCGGGACTC GCACCGCAGCTGTTGATTTTCGGCGCCAGTACGCTTCAGGGCGAAGTACC CACCGCAGCTGTTGATTTTCGCCCCCAGTACGCTTCAGGCCGAAGTACC GTCCAGGTTCAGTGGGTCAGGTTCTGGCACCGATTTTACGCTCACGATATO TCCAGGTTCAGTGGGTCAGGTTCTGGCACCGATTTTACGCTCACGATATC CAGTCTCCAACCGGAGGATTTTGCTACTTATTACTGCCAGCAGGCTAAGT CAGTCTCCAACCGGAGGATTTTGCTACTTATTACTGCCAGCAGGCTAAGTA TTTTCCATACACATTTGGCCAGGGGACAAAGTTGGAGATCAAAGCGGCCG FTTTCCATACACATTTGGCCAGGGGACAAAGTTGGAGATCAAAGCGGCCG CAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCA AGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG AGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGG AGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGG AGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGG CCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCO CCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCC TTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCG TTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCG TTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAG FTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAG ATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCAC ATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCAC GGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAAC GAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGAC GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCA GCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCA GGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTAC TCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG GCATATGCAAGCACTCCCACCCCGG LTG2204: LP-16P16-CD8TM-41BB-CD3zeta LP-16P16-CD8 TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:64) 64)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQFS QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQ0 GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT ILEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKR RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR

FIGURE 2G

SUBSTITUTE SHEET (RULE 26)

LTG2205: LP-16P20-CD8 LTG2205: LP-16P20-CD8 TM-41BB-CD3zet TM-41BB-CD3zeta nucleic nucleic acid acid sequence sequence (SEQ ID(SEQ NO: ID NO: 73)

ATGCTGCTCCTCGTAACCTCTCTTCTTCTTTGTGAGTTGCCACATCCAGCAT ATGCTGCTCCTCGTAACCTCTCTTCTTCTTTGTGAGTTGCCACATCCAGCAT TTCTTCTGATACCTCAAGTTCAACTCCAGCAGAGTGGTCCAGGTTTGGTAA ITCTTCTGATACCTCAAGTTCAACTCCAGCAGAGTGGTCCAGGTTTGGTAA AACCCAGCCAGACTCTCTCATTGACGTGTGCCATATCAGGTGATTCAGTTT AACCCAGCCAGACTCTCTCATTGACGTGTGCCATATCAGGTGATTCAGTT CCTCTAATAGCGCGGCATGGAATTGGATCAGGCAAAGCCCTAGTCGCGGG CCTCTAATAGCGCGGCATGGAATTGGATCAGGCAAAGCCCTAGTCGCGGC CTGGAGTGGCTCGGCCGGACATACTACCGCTCAAAGTGGTACAACGACTA CTGGAGTGGCTCGGCCGGACATACTACCGCTCAAAGTGGTACAACGACTA CGCCGTCAGCGTAAAATCTCGGATTACCATTAACCCGGATACTTCCAAAA CGCCGTCAGCGTAAAATCTCGGATTACCATTAACCCGGATACTTCCAAA ACCAATTCTCCCTGCAGCTTAACAGTGTCACGCCGGAAGATACGGCCGTT TATTACTGCGCACAAGAGGTGGAACCGCACGACGCCCTCGATATCTGGGO TATTACTGCGCACAAGAGGTGGAACCGCACGACGCCCTCGATATCTGGGG CCAAGGCACTATGGTGACCGTCAGTAGCGGAGGGGGGGGTTCCGGAGGA GGCGGCTCTGGTGGCGGAGGATCTGATATCCAAATGACCCAATCACCGTO GGCGGCTCTGGTGGCGGAGGATCTGATATCCAAATGACCCAATCACCGTC TTCAGTATCAGCTTCTGTTGGTGACAAAGTTACGATTACCTGTCGAGCGTC ITCAGTATCAGCTTCTGTTGGTGACAAAGTTACGATTACCTGTCGAGCGTC ACAGGACGTTTCTGGTTGGTTGGCTTGGTATCAGCAAAAACCAGGGCT ACAGGACGTTTCTGGTTGGTTGGCTTGGTATCAGCAAAAACCAGGGCTTC CGCCTCAGTTGCTTATTTTTGGGGCATCTACTTTGCAGGGAGAGGTGCCCT CGCCTCAGTTGCTTATTTTTGGGGCATCTACTTTGCAGGGAGAGGTGCCCT CCCGGTTCTCCGGCAGTGGGAGCGGCACCGATTTTACACTTACCATCTCTT CCCGGTTCTCCGGCAGTGGGAGCGGCACCGATTTTACACTTACCATCTCTI CCTTGCAACCCGAAGACTTTGCGACGTACTATTGCCAGCAGGCAAAGTAT CCTTGCAACCCGAAGACTTTGCGACGTACTATTGCCAGCAGGCAAAGTAT TTTCCCTACACTTTTGGACAAGGGACTAAACTTGAAATCAAGGCGGCCGC TTTCCCTACACTTTTGGACAAGGGACTAAACTTGAAATCAAGGCGGCCGC AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCGTGCATACCCGGGGGCTGGACTITGCCTGCGATATCTACATTTGGGCC GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTE TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATOCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACO FTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACE AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACC GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTC CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG

LTG2205: LP-16P20-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 74)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSS MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGC QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLI GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF BASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACI KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRI RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR

FIGURE 2H SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011 PCT/US2018/056011

10/28

LTG2206: LP-16P2-CD8 LTG2206: TM-41BB-CD3zeta nucleic LP-16P2-CD8TM-41BB-CD3zeta acid acid nucleic sequence (SEQ ID(SEQ sequence NO: ID NO: 83)

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT TCCTGCTTATTCCCCAAGTCCAGCTCCAACAATCCGGACCCGGACTTGTTA TCCTGCTTATTCCCCAAGTCCAGCTCCAACAATCCGGACCCGGACTTGTIA AGCCGTCTCAGACGTTGTCACTCACATGCGCCATCAGTGGCGATAGCGTC AGCCGTCTCAGACGTTGTCACTCACATGCGCCATCAGTGGCGATAGCGTG TCCAGCAACAGTGCCGCATGGAATTGGATACGACAGAGCCCTTCCCGAGG TCCAGCAACAGTGCCGCATGGAATTGGATACGACAGAGCCCTTCCCGAGG ATTGGAATGGCTGGGACGAACGTACTATAGGTCCAAGTGGTATAACGACT ACGCGGTGTCAGTTAAATCTCGGATTACTATAAATCCCGACACTTTTAAGA ACGCGGTGTCAGTTAAATCTCGGATTACTATAAATCCCGACACTTTTAAGA ATCAGTTTTCCCTGCAACTCAATTCAGTCACACCGGAAGATACGGCAGTG ATCAGTTTTCCCTGCAACTCAATTCAGTCACACCGGAAGATACGGCAGT TACTATTGCGCTCAAGAAGTTGAGCCACATGATGCGCTGGATATTTGGGG TCAGGGGACTATGGTGACGGTAAGCAGTGGGGGCGGGGGCAGTGGCGGA ICAGGGGACTATGGTGACGGTAAGCAGTGGGGGCGGGGGCAGTGGCGGA GGTGGCAGCGGGGGCGGTGGAAGCGACATTAAGATGACTCAGTCTCCGTC GGTGGCAGCGGGGGCGGTGGAAGCGACATTAAGATGACTCAGTCTCCGTC TTCAGTTTCCGCCTCCGTAGGGGACAAGGTTACAATTACTTGTCGCGCATO FTCAGTTICCGCCTCCGTAGGGGACAAGGTTACAATTACTTGTCGCGCATC TCAGGATGTCTCAGGTTGGCTGGCTTGGTATCAACAGAAGCCTGGCCTCG ICAGGATGTCTCAGGTTGGCTGGCTTGGTATCAACAGAAGCCTGGCCTCG CCCCTCAGCTTCTCATATTCGGGGCTAGTACCCTGCAAGGAGAAGTCCCG CCCCTCAGCTTCTCATATICGGGGCTAGTACCCTGCAAGGAGAAGTCCCC AGCAGGTTTTCCGGTTCAGGGTCCGGGACAGACTTTACCTTGACCATCAG AGCAGGTTTTCCGGTTCAGGGTCCGGGACAGACTTTACCTTGACCATCAG CTCCCTGCAACCGGAGGACTTCGCGACCTACTATTGTCAACAGGCGAAGT TCCCTGCAACCGGAGGACTTCGCGACCTACTATTGTCAACAGGCGAAGT ACTTCCCCTACACGTTCGGGCAAGGGACTAAGCTCGAAATCAAGGCGG ACTTCCCCTACACGTTCGGGCAAGGGACTAAGCTCGAAATCAAGGCGGCC GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGC AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTC AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG GAGCCGTGCATACCCGGGGGCTGGACTITGCCTGCGATATCTACATTTGG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACO GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA GATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA GATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTC CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTC AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA CTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG. CTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG LTG2206: LP-16P2-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 84)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSI SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTFKNQFSL QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GGSDIKMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACOI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRJ RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR YQGLSTATKDTYDALHMQALPPR

FIGURE 2I SUBSTITUTE SHEET (RULE 26) wo WO 2019/079249 PCT/US2018/056011

11/28

LTG2207: LP-16P6-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 93)

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT TCCTGCTTATTCCCCAAGTACAACTCCAGCAATCAGGGCCTGGCCTTGTC TCCTGCTTATTCCCCAAGTACAACTCCAGCAATCAGGGCCTGGCCTTGTCA AGCCGAGTCAAACCTTGAGTTTGACGTGTGCCATCAGCGGTGACTCTGTC AGCCGAGTCAAACCTTGAGTTTGACGTGTGCCATCAGCGGTGACTCTGTC AGTTCAAACTCCGCAGCTTGGAACTGGATTCGGCAGTCCCCCTCCAGGGG AGTTCAAACTCCGCAGCTTGGAACTGGATTCGGCAGTCCCCCTCCAGGGE CCTCGAATGGCTTGGACGGACGTACTACAGATCAAAATGGTACAACGACT ACGCAGTCAGTGTAAAATCAAGGATTACGATAAACCCTGATACGAGTAAA AACCAGTTCTCTCTCCAACTGAACAGCGTCACACCGGAAGATACAGCCGT AACCAGTTCTCTCTCCAACTGAACAGCGTCACACCGGAAGATACAGCCG GTATTACTGTGCTCAGGAAGTGCAACCTGACGACGCATTTGACATCTGGG GTCAGGGCACGATGATCACCGTGAGTAGTGGAGGAGGAGGCAGTGGGGG GTCAGGGCACGATGATCACCGTGAGTAGTGGAGGAGGAGGCAGTGGGGG AGGCGGTTCTGGCGGGGGTGGGTCTGATATACAGATGACACAGAGTCCCT GGCGGTTCTGGCGGGGGTGGGTCTGATATACAGATGACACAGAGTCCCT CCTCAGTITCCGCCTCTGTTGGAGATAAGGTGACAATTACATGCAGGGCG CCTCAGTTTCCGCCTCTGTTGGAGATAAGGTGACAATTACATGCAGGGCG TCCCAAGATGTTTCTGGATGGCTCGCATGGTACCAACAGAAGCCAGGACT TCCCAAGATGTTTCTGGATGGCTCGCATGGTACCAACAGAAGCCAGGACT CGCCCCTCAGCTCCTCATTAGCGGCGCTAGCACTCTCCAAGGGGGAGTAC CGCCCCTCAGCTCCTCATTAGCGGCGCTAGCACTCTCCAAGGGGGAGTAC CGAGCAGGTTCTCTGGGTCCGGAAGTGGGACGGACTTTACCCTGACAATA GAGCAGGTTCTCTGGGTCCGGAAGTGGGACGGACTTTACCCTGACAATA FCCTCCCTTCAGCCAGAAGACTTCGCAACCTACTATTGCCAACAGGCGAA CCTCCCTTCAGCCAGAAGACTTCGCAACCTACTATTGCCAACAGGCGAA AAATTTCCCTTACACGTTCGGCCAAGGAACTAAACTTGAAATCAAGGCGG AAATTTCCCTTACACGTTCGGCCAAGGAACTAAACTTGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTITGCCTGCGATATCTACATTTO GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTO AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCC ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG LTG2207: LP-16P6-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 94)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMITVSSGGGGSGGGGSGG0 QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMITVSSGGGGSGGCGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG STLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT ASTLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI) LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR

FIGURE 2J

SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

12/28

LTG2208: LP-16P10-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 103)

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT TGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAAGTGCAGTTGCAACAGTCTGGACCAGGCCTCGTAA TCCTGCTTATTCCCCAAGTGCAGTTGCAACAGTCTGGACCAGGCCTCGTA4 AACCTTCTCAAACTTTGTCACTCACTTGTGCCATCTCAGGGGACAGTGTCA ACCTTCTCAAACTTTGTCACTCACTTGTGCCATCTCAGGGGACAGTGTCA GTTCCAACAGTGCGGCATGGAATTGGATTAGGCAATCCCCCTCTCGAGGT GTTCCAACAGTGCGGCATGGAATTGGATTAGGCAATCCCCCTCTCGAGGI CTGGAATGGCTTGGGCGGACTTACTACCGAAGTAAGTGGTACAACGATTA CTGGAATGGCTTGGGCGGACTTACTACCGAAGTAAGTGGTACAACGATTA TGCAGTTTCTGTAAAATCACGAATCACTATAAATCCGGACACTTCTAAGA TGCAGTTTCTGTAAAATCACGAATCACTATAAATCCGGACACTTCTAAGA ATCAGTTCTCTTTGCAGCTTAACTCTGTTACTCCTGAAGACACAGCCGTAT ATCAGTTCTCTTTGCAGCTTAACTCTGTTACTCCTGAAGACACAGCCGTAT ATTACTGTGCTCAAGAGGTAGAGCCGCAAGATGCCTTCGACATCTGGGGC ATTACTGTGCTCAAGAGGTAGAGCCGCAAGATGCCTTCGACATCTGGGGC CAAGGGACTATGGTGACAGTAAGCTCCGGAGGTGGGGGATCAGGGGG/ CAAGGGACTATGGTGACAGTAAGCTCCGGAGGTGGGGGATCAGGGGGAG GTGGGTCCGGTGGTGGTGGCTCTGACATACAGATGACACAGTCCCCTAGC TCTGTGTCAGCAAGTGTCGGTGACAAGGTTACGATAACGTGCAGGGCCAG TCAAGATGTGTCAGGATGGTTGGCGTGGTACCAACAGAAACCCGGCTTGG TCAAGATGTGTCAGGATGGTTGGCGTGGTACCAACAGAAACCCGGCTTGC CACCGCAGCTITTGATATTCGGCGCGTCCACACTCCAAGGCGAAGTGCCTI CACCGCAGCTTTTGATATICGGCGCGTCCACACTCCAAGGCGAAGTGCCTI CTCGGTTTTCTGGAAGCGGCAGCGGGACGGACTTTACTTTGACAATATCCT CTCGGTTTTCTGGAAGCGGCAGCGGGACGGACTTTACTTTGACAATATCCT CCCTCCAACCCGAGGATTTCGCGACGTATTATTGCCAGCAAGCAAAATAC CCCTCCAACCCGAGGATTTCGCGACGTATTATTGCCAGCAAGCAAAATAC TTCCCATACACCTTCGGGCCTGGGACCAAACTGGAGATCAAAGCGGCCGC FTCCCATACACCTTCGGGCCTGGGACCAAACTGGAGATCAAAGCGGCCGC AACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAA GCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGA GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGC GCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTT TACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT FACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTT CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA CATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGA TTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCAC< ITCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACE GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACG GTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACE AGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACG CGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAG GAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACT CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG CAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACG GGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTG CATATGCAAGCACTCCCACCCCGG CATATGCAAGCACTCCCACCCCGG LTG2208: LP-16P10-CD8 TM-41BB-CD3zet TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:104) 104)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSI SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGPGTKL ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGPGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR

FIGURE 2K FIGURE 2K SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

13/28 13/28

LTG2209: LP-16P17-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 113)

ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC' ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT CCTGCTTATTCCCCAGGTACAGCTTCAACAGAGTGGGCCGGGACTGGTC FCCTGCTTATTCCCCAGGTACAGCTTCAACAGAGTGGGCCGGGACTGGTC AAACACTCCCAAACACTTTCTCTGACGTGCGCTATATCAGGTGACTCTGTT AAACACTCCCAAACACTTICTCTGACGTGCGCTATATCAGGTGACTCTGT TCATCTAATTCTGCTGCGTGGAACTGGATTCGACAATCTCCCAGTCGCGGG TTGGAATGGCTGGGACGAACATATTATCGGTCTAAGTGGTATAACGATTA TGCTGTATCTGTTAAATCTCGAATTACGATTAATCCTGACACCTCCAAGAA TGCTGTATCTGTTAAATCTCGAATTACGATTAATCCTGACACCTCCAAGA CCAGTTCTCCCTCCAGTTGAACTCAGTCACACCGGAAGACACTGCGGTCT CCAGTTCTCCCTCCAGTTGAACTCAGTCACACCGGAAGACACTGCGGTCT ACTATTGCGCTCAAGAAGTCGAGCCACATGATGCATTCGACATCTGGGGC ACTATTGCGCTCAAGAAGTCGAGCCACATGATGCATTCGACATCTGGGGC CAGGGAACGATGGTCACCGTCAGCAGTGGCGGCGGCGGATCTGGGGGTG GCGGTTCTGGCGGTGGAGGATCAGACATACAAATGACGCAGAGTCCCTCA GCGGTTCTGGCGGTGGAGGATCAGACATACAAATGACGCAGAGTCCCTC AGTGTGTACGCGAGTGTGGGGGATAAGGTAACTATTACGTGCAGAGCGTC AGTGTGTACGCGAGTGTGGGGGATAAGGTAACTATTACGTGCAGAGCGTC ACAGGATGTTAGTGGATGGCTTGCCTGGTATCAGCAGAAGCCAGGCCTTC CTCCACAGCTCCTTATCAGTGGTGCTTCTACACTTCAGGGCGAGGTTCCGA CTCCACAGCTCCTTATCAGTGGTGCTTCTACACTICAGGGCGAGGTTCCG GTAGATTCTCTGGTTCTGGATCTOGTACTGACTTCACTCTTACAATTTCTTC GTAGATTCTCTGGTTCTGGATCTGGTACTGACTICACTCTTACAATTTCTTC TTTGCAACCAGAAGACTTTGCGACTTATTACTGCCAACAGGCCAAATACTT TTGCAACCAGAAGACTTTGCGACTTATTACTGCCAACAGGCCAAATACTT CCCTTATACATTTGGCCAAGGTACCAAGTTGGAGATAAAGGCGGCCGCAA TACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAG CTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGC CAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGC GTGCATACCCGGGGGCTGGACTITGCCTGCGATATCTACATTTGGGCCCC CGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCC GCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTA GCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTA CTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCA TGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTO FGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTC CCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGT CCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAG CCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAG CTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCG ACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGA GACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGA AGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCA GAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGG CTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCA CTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTOCA TATGCAAGCACTCCCACCCCGG LTG2209: LP-16P17-CD8 TM-41BB-CD3zet TM-41BB-CD3zetaamino aminoacid acidsequence sequence(SEQ (SEQID IDNO: NO:114) 114)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLT MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSI SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPHDAFDIWGQGTMVTVSSGGGGSGGGGSGGG QLNSVTPEDTAVYYCAQEVEPHDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVYASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG GSDIQMTQSPSSVYASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRG PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR

FIGURE 2L SUBSTITUTE SHEET (RULE 26)

LTG2210: LTG2210:LP-16P20v2-CD8 TM-41BB-CD3zeta nucleic LP-16P20v2-CD8TM-41BB-CD3ze acid nucleic sequence acid (SEQ (SEQ sequence ID ID NO: 123)

ATGCTTCTITTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCT ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCC TCCTGCTTATTCCCCAAGTACAACTTCAACAGTCTGGGCCTGGGCTTGTAA FCCTGCTTATTCCCCAAGTACAACTTCAACAGTCTGGGCCTGGGCTTGTA AACCTAGCCAAACTCTGTCCCTCACGTGCGCGATTTCAGGGGACAGTGTA AACCTAGCCAAACTCTGTCCCTCACGTGCGCGATTTCAGGGGACAGTGTA AGTTCCAACTCAGCCGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGG AGTTCCAACTCAGCCGCATGGAACTGGATCAGGCAGTCACCTTCAAGGGG GCTCGAATGGCTTGGCCGAACGTACTACAGGAGTAAGTGGTACAACGATT ATGCAGTGTCTGTGAAATCACGGATTACTATCAATCCCGACACGTCCAAG ATGCAGTGTCTGTGAAATCACGGATTACTATCAATCCCGACACGTCCAAC AACCAGTTCTCTCTGCAACTCAACTCAGTGACACCAGAGGATACGGCCGT AACCAGTTCTCTCTGCAACTCAACTCAGTGACACCAGAGGATACGGCCGT TTACTATTGTGCACAGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGG ITACTATTGTGCACAGGAAGTGCAACCTGATGATGCCTTTGACATTTGGGG TCAGGGCACGATGGTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGG CAGGGCACGATGGTTACGGTAAGCTCTGGGGGAGGCGGCAGTGGAGGG GGAGGTAGTGGGGGAGGGGGATCTGATATACAGATGACACAAAGCCCO GGAGGTAGTGGGGGAGGGGGATCTGATATACAGATGACACAAAGCCCGT ATCCGTCAGTGCTTCAGTTGGTGATAAAGTAACCATTACGTGCCGCGCT CATCCGTCAGTGCTTCAGTTGGTGATAAAGTAACCATTACGTGCCGCGCTT CCCAAGACGTTAGCGGATGGTTGGCTTGGTATCAACAAAAACCGGGGTTG ACTCCGCAACTCCTCATATCCGGTGCGAGTACGCTCCAAGGCGAAGTC6 GCTCCGCAACTCCTCATATCCGGTGCGAGTACGCTCCAAGGCGAAGTCCC TAGCAGATTITCCGGGAGCGGTTCCGGTACAGATTTCACGTTGACCATTAG TAGCAGATTTTCCGGGAGCGGTTCCGGTACAGATTICACGTTGACCATTAG CTCTCTCCAGCCCGAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAA CTCTCTCCAGCCCGAAGATTTTGCAACCTACTATTGCCAACAGGCCAAAA ATTITCCATATACATTTGGTCAAGGCACTAAGCTCGAAATCAAAGCGGCC ATTTTCCATATACATTTGGTCAAGGCACTAAGCTCGAAATCAAAGCGGCC GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGC GCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGC AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG AAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTG GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGO GAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGGCTGGTCATCACO GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCC CTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCO GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC. GTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCA ATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTO CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTC AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA AGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTA CTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGAC GGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTT GCATATGCAAGCACTCCCACCCCGG GCATATGCAAGCACTCCCACCCCGG LTG2210: LP-16P20v2-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 124)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN LLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFS SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL CNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMVTVSSGGGGSGGGGSGC QLNSVTPEDTAVYYCAQEVQPDDAFDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIS GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIS GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKNFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC IWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKR RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKOKMABAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR

FIGURE 2M FIGURE 2M SUBSTITUTE SHEET (RULE 26)

LTG2216: LP-16P1-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 133)

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCI TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGATATTAGCGGGGACTCA AAGCCGTCCCAGACTCTGAGCCTGACTTGCGATATTAGCGGGGACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA IACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAATCGAACCGCACGACGCCTTCGACATTTGG FGTACTACTGCGCACAAGAAATCGAACCGCACGACGCCTTCGACATTTGG GACCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGTGATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGO TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT TGGCTCCTCAACTGCTGATCTCCGGCGCCAGCTCACTTCAGGGGGGGGTG TGGCTCCTCAACTGCTGATCTCCGGCGCCAGCTCACTICAGGGGGGGGTG CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTICACCCTGACCATC AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAJ GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTO TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCA0 GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCA0 ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG LTG2216: LTG2216: LP-16P1-CD8 LP-16P1-CD8 TM-41BB-CD3zeta TM-41BB-CD3zeta amino amino acid acid sequence sequence (SEQ (SEQ ID ID NO: NO: 134) 134)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCDISGDSVSS) MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCDISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEIEPHDAFDIWDQGTMVTVSSGGGGSGGGGSGGG QLNSVTPEDTAVYYCAQEIEPHDAFDIWDQGTMVTVSSGGGGSGGGGSGGG GSVIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG GSVIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLISG SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQC ASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR

FIGURE 2N

SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

16/28

LTG2217:LP-16P3v2-CD8 LTG2217: LP-16P3v2-CD8TM-41BB-CD3zeta nucleic TM-41BB-CD3zeta nucleic acid acid sequence sequence (SEQ ID(SEQ NO: ID NO: 143)

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC TTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT AAGCACTCCCAGACTCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAC AAGCACTCCCAGACTCTGAGCCTGGCCTGCGCGATTAGCGGGGACTCAG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAGTGCAGCCGCAGGACGCCCTGGACATTTGG TGTACTACTGCGCACAAGAAGTGCAGCCGCAGGACGCCCTGGACATTTGG GGGCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGGCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTTCGTGTCCGCATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGO TCCTTCGTGTCCGCATCCGTGGGCGATAAGGTCATTATTACCTGTAGAGCG TCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCTT GGCTCCTCAACTGCTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGC GCTCCTCAACTGCTGATCTCCGGCGCCAGCACTCTTCAGGGGGAAGTGC ATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATCA CATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTICACCCTGACCATCA GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA TACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGGC AGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCA GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCAG ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG LTG2217: LP-16P3v2-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 144)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLACAISGDSVSSN LLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKHSQTLSLACAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVQPQDALDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVQPQDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSFVSASVGDKVIITCRASQDVSGWLAWYQQKPGLAPQLLISG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI EIKAAATTTPAPRPPTPAPTIASOPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRP PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR

FIGURE 20

SUBSTITUTE SHEET (RULE 26) wo 2019/079249 WO PCT/US2018/056011

17/28

LTG2218: LP-16P8-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 153)

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCAATTAGCGGGGACTCAGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCAATTAGCGGGGACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATICGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGGE GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATACCGAC GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATACCGAC TACGCCGTGTCCGTGAAGAATCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGGE TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGC TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCO TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAG ICCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATIACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACTCTTCAGGGGGAAGTG FGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACTCTICAGGGGGAAGTG CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATO AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCA GTACTTCCCCTATACCTTCGGAAGAGGCACTAAGCTGGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATC GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATITO IGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAG CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACC ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TGCATATGCAAGCACTCCCACCCCGG TTGCATATGCAAGCACTCCCACCCCGG LTG2218: LP-16P8-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 154)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSI MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN AAWNWIRQSPSRGLEWLGRTYYRSKWYTDYAVSVKNRITINPDTSKNQI SAAWNWIRQSPSRGLEWLGRTYYRSKWYTDYAVSVKNRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFO GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGRGTKL ASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGRGTKL EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY EIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRJ PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR OPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR GLSTATKDTYDALHMQALPPR

FIGURE 2P

SUBSTITUTE SHEET (RULE 26)

LTG2219: LP-16P13-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 163)

ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGC ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGT FTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCCATTAGCGGGAACTCAGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCCATTAGCGGGAACTCAGT CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGO CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGA TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA FACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCO GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGG TGTACTACTGCGCACAAGAAGTGGAACCGCAGGACGCCTTCGACATTTGC GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GGACAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT TGGCTCCTCAACTGCTGATCTTTGGCGCCAGCACTCTTCAGGGGGAGGTGC CATCACGCTTCTCCGGAGGTGGTTCCGGCACCGACTTCACCCTGACCATCA GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA GCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAAG CACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCG FACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGGC CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCG CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT CAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGT GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTT GGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCA GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTG CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCO ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGC TTGCATATGCAAGCACTCCCACCCCGG LTG2219: LTG2219: LP-16P13-CD8 LP-16P13-CD8 TM-41BB-CD3zeta TM-41BB-CD3zeta amino amino acid acid sequence sequence (SEQ (SEQ ID ID NO: NO: 164) 164)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGNSVSS) MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGNSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGG QLNSVTPEDTAVYYCAQEVEPQDAFDIWGQGTMVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG GSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIFG SLQGEVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK ASTLQGEVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGTK LEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR

FIGURE 2Q

SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011

19/28 19/28

LTG2220: LP-16P15-CD8 TM-41BB-CD3zeta nucleic acid sequence (SEQ ID NO: 173)

TGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGG ATGTTGCTGCTCGTGACCTCGCTCCTTCTGTGCGAGCTGCCCCATCCGGCT TTTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC ITTCTGCTCATCCCTCAAGTGCAGCTGCAGCAGTCCGGTCCTGGACTGGTC AGCCGTCCCAGACTCTGAGCCTGACTTGCGCGATTAGCGGGGACTCAGT AAGCCGTCCCAGACTCTGAGCCTGACTTGCGCGATTAGCGGGGACTCAGT CTCGTCCAATICGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG CTCGTCCAATTCGGCGGCCTGGAACTGGATCCGGCAGTCACCATCAAGGG GCCTGGAATGGCTCGGGCGCACTTACTACCGGTCCAAATGGTATAACGAC TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA TACGCCGTGTCCGTGAAGTCCCGGATCACCATTAACCCCGACACCTCGAA GAACCAGTTCTCACTCCAACTGAACAGCGTGACCCCCGAGGATACCGCGG TGTACTACTGCGCACAAGAAGTGGAACCGCACGACGCCCTGGACATTTGG GGTCAGGGAACGATGGTCACAGTGTCGTCCGGTGGAGGAGGTTCCGGAG GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC GCGGTGGATCTGGAGGCGGAGGTTCGGATATCCAGATGACCCAGAGCCCC TCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC FCCTCGGTGTCCGCATCCGTGGGCGATAAGGTCACCATTACCTGTAGAGC GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGCT GTCCCAGGACGTGTCCGGATGGCTGGCCTGGTACCAGCAGAAGCCAGGC TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACACTTCAGGGGGAGGTG TGGCTCCTCAACTGCTGATCTTCGGCGCCAGCACACTICAGGGGGAGGTG CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC CCATCACGCTTCTCCGGATCCGGTTCCGGCACCGACTTCACCCTGACCATC AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCAA AGCAGCCTCCAGCCTGAGGACTTCGCCACTTACTACTGCCAACAGGCCA GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG GTACTTCCCCTATACCTTCGGACAAGGCACTAAGCTGGAAATCAAGGCGG CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATO CCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATE GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG GCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATITG TGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTG GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC GGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCAC CCTITACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC CGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC AGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTC ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACA ACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCG ACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCO CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT CAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCT ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACG ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCO ACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCC TTGCATATGCAAGCACTCCCACCCCGG TTGCATATGCAAGCACTCCCACCCCGG LTG2220: LP-16P15-CD8 TM-41BB-CD3zeta amino acid sequence (SEQ ID NO: 174)

MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSN SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFS SAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSL LNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSG QLNSVTPEDTAVYYCAQEVEPHDALDIWGQGTMVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLE GGSDIQMTQSPSSVSASVGDKVTITCRASQDVSGWLAWYQQKPGLAPQLLIF GASTLQGEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAKYFPYTFGQGT KLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR

FIGURE 2R FIGURE 2R

SUBSTITUTE SHEET (RULE 26)

@@@@@@@@@@@ 40 60 90 20 70 30 50 80 10 o

% transduction % transduction

@@@@@@@ @@@@@@

CD22_16p CD22_16p CD22_25p CD22_25p CD22_115 CD22_11s CD22_12s CD19_1538

CD22_12s CD19_1538 CD22_16p CD22_16p CD22_25p CD22_25p CD22_11s CD22_11s CD22_12s CD22_12s CD19_1538 CD19_1538

Protein L CD22_FC

Figure 3

SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011

21/28

CD22 CD22 CD22 CD22 CD22 CD22 CD22 CD19 Mock Mock GFP 25p 16p 11s 12s 1538 100 100

80

80 60 %lysis

RAJI 40

20

0

-20 -20

CD22 CD22 CD22 CD22 CD22 CD22 CD19 Mock GFP 25p 25p 16p 11s 12s 1538 100

80

%lysis 60

40

REH 20

0 -20 -20

CD22 CD22 CD22 CD22 CD19 Mock GFP 25p 16p 11s 12a 1538 100 100

80

60 %lysis

40 40

NALM6 20

0 -20

CD22 CD22 CD22 CD22 CD19 Mock GFP 25p 16p 11s 12s 1538 100

80

%lysis 80 60

k562 40

20

0 2.5:1 2.5:1 2.5:1 2.5:1 20:1 10:1 5:1 20:1 10:1 5:1 20:1 10:1 5:1 20:1 2.5:1 2.5:1 2.5:1 20:1 10:1 5:1 1:01 1:5 20:1 1:01 5:1 20:1 10:1 5:1

-20

FIGURE 4

SUBSTITUTE SHEET (RULE 26)

1.E+08 1.E+08

1.E+07 (PHOTON/SEC/CM2/SR)

AVERAGE RADIANCE

1.E+06

1.E+05

1.E+04

1.E+03

6 11 18 25 32 39 DAYS POST TUMOR IMPLANT PBS UTD CAR19 16p m971

Figure 5

SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011 PCT/US2018/056011

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2200 (m971) 2202 (16p) 10³ UTD 10³ 10 3 103 10³ FL1-A:: VioBlue-A

Q1 Q2 FL1-A :: VioBlue-A

Q1 Q2 FL1-A:: VioBlue-A

Q1 Q2 79.1. 79.1 1.89 22.8 54.9 50.4 30.5 10² 102 102 10² 102 10²

10¹ 10)1 1 10 10 10

10 0 10 100 10 100 10 Q4 Q3 Q4 Q3 Q4 Q3 Q3 0.39 8.95 8.95 16.1 3.04 3.04 18.6 18.6 13.4 13.4 16.1 10¹ 10-1 10-11 10-1 10¹ 10¹ 10-1 100 10¹ 101 102 10² 103 10³ 10-1 100 101 10¹ 102 10² 103 10³ 10-1 100 10¹ 102 10² 10³ 103 10 10¹ 10 10¹ 10 10)

FL4-A FL4-A:::PE-A PE-A FL4-A :: PE-A FL4-A ::PE-A FL4-A PE-A

2216 (16p1) 2206 (16p2) 2217 (16p3v2) 3 10³ 10 103 10³ 103 10³ FL1-A:: VioBlue-A

Q1 FL1-A:: VioBlue-A

Q1 Q2 Q2 FL1-A:: VioBlue-A

Q1 Q2 Q2 45.8 32.6 52.1 28.8 28.8 62.0 19.4 102 10² 102 10² 102 10²

10¹1 10) 10¹ 1 1 10 10

10° 0 10 0 10 10 10 10 Q4 Q3 Q4 Q3 Q4 Q3 17.7 3.89 3.89 16.5 2.59 17.0 1.68 1 10-1 10¹ 10 10- 10¹ 1 10 1 1 10-1 10¹ 100 10¹ 10² 102 103 10³ 10-1 10¹ 100 10¹ 102 10² 103 10³ 10-1 10¹ 100 10¹ 102 10² 10³ 10 10 10 10 10 10 10 FL4-A ::PE-A FL4-A PE-A FL4-A:::PE-A FL4-A PE-A FL4-A ::PE-A FL4-A PE-A

2207 (16p6) 2218 (16p8) 2208 (16p10) 3 10³ 10³ 103 103 10³ 10 Q1 FL1-A:: VioBlue-A

Q1 FL1-A :: VioBlue-A

Q1 FL1-A:: VioBlue-A

Q2 Q2 Q2 42.8 42.8 40.6 40.6 42.9 40.6 52.6 27.9 10² 102 102 10² 102 10²

10¹1 1 1 10 10 10

0 100 10 10 10 10 10 Q4 Q3 Q4 Q3 Q4 Q3 12.8 3.82 12.2 4.33 17.1 2.39 10¹ 10-1 10¹ 10-1 10¹ 10 superscript(3) 10 1 1 10-1 1 10¹ 10- 100 101 10¹ 102 10² 10³ 10¹ 100 10¹ 102 10² 103 10³ 10¹ 100 10¹ 102 10² 10³ 103 10 10 10 10 10 10 FL4-A :: FL4-A PE-A : PE-A FL4-A :: PE-A FL4-A:: PE-A FL4-A:: PE-A FL4-A PE-A

FIGURE FIGURE 66

SUBSTITUTE SHEET (RULE 26)

2219 (16p13) 2220 (16p15) 2209 (16p17) 103 10³ 103 10³ 103 10³ FL1-A :: VioBlue-A

Q1 Q2 FL1-A:: VioBlue-A

Q1 Q1 Q2 FL1-A :: VioBlue-A

Q1 Q2 42.1 47.3 34.0 36.6 47.3 47.3 39.7 102 10² 102 10² 102 10²

10)1 10 10¹1 10 10 1

100 100 100 10 Q3 10 Q3 10 Q3 Q4 Q4 Q4 4.21 2.90 4.62 14.0 15.7 11.5 10-1 10-1 10-1 10¹ 10¹ 10¹ 10 superscript(3) 10 superscript(3)

10-1 100 101 10¹ 102 10² 10³ 10-1 100 1 10¹ 102 10² 103 10³ 10-1 100 10¹ 101 102 10² 10³ 10¹ 10 10¹ 10 10 10¹ 10 FL4-A ::PE-A FL4-A PE-A FL4-A: FL4-A PE-A PE-A FL4-A: PE-A FL4-A PE-A

2205 (16p20) 1538 (FMC63) 103 GFP 103 10³ 10³ 103 10³ FL1-A :: VioBlue-A

Q1 Q2 FL1-A:: VioBlue-A

Q5 Q6 FL1-A:: VioBlue-A

Q1 Q2 31.3 53.1 53.1 11.7 66.6 66.6 24.2 53.2 102 10² 102 10² 102 10²

101 10¹ 1 1 10 10 10 10

100 100 100 10 10 Q7 10 Q3 Q4 Q3 Q8 Q4 6.25 13.0 9.38 9.38 9.34 9.34 8.65 8.65 13.3 10-71 10-11 10-1 1 10¹ 10 10 10-1 101 1 101 100 10¹ 10¹ 10 10210³ 10² 10-1 10¹ 100 10¹ 102 10² 103 10³ 10-1 10¹ 100 10¹ 102 10² 103 10³ 10 10 10 10 FL4-A :: PE-A FL4-A:: PE-A FL4-A :: PE-A FL4-A FL4-A:::PE-A PE-A

CD4 FIGURE 6 (CONT) CAR CAR

SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011

25/28

RAJI 10:1 100 5:1

2.5:1 80 %lysis

60

40

20

0 utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p13 16p15 16p17 16p20

10:1

REH REH 5:1 5:1

100 2.5:1

80 %lysis

60 60

40

20

0 utd GFP 1538 m971 16p 16p1 16p216p3y2 16p6 16p8 16p10 16p13 16p15 16p17 16p20

K562 10:1 100 5:1

2.5:1 80 %lysis

60 60

40 40

20 20

0 utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p13 16p15 16p17 16p20

FIGURE 7A SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011

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K562-CD19 10:1 100 5:1

2.5:1 80 %lysis

60

40

20

0 utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p13 16p15 16p17 16p20

10:1

MW 5:1 5:1

2.5:1 K562-CD22 100 100

80 %lysis

60

40

20

0 utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p13 16p15 16p17 16p20

FIGURE 7B

SUBSTITUTE SHEET (RULE 26)

WO wo 2019/079249 PCT/US2018/056011

27/28 RAJI RAJI IFNg REH T cells only 12000 8000 4000 2500 pg/ml

2000

1500

1000

500

0 16p20 tumor only 16p13 16p15 16p17 utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10

RAJI IL2 REH T cells only 2500 2000 1500 1000

pg/ml

600

400 400

200

0 16p20 tumor only utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p1316p1516p17

RAJI REH REH T cells only TNFa 2500 2000 1500 1000

pg/ml

600

400

200

0 16p20 tumor only utd GFP 1538 m971 16p 16p1 16p216p3v2 16p6 16p8 16p10 16p13 16p1516p17

Figure 8

SUBSTITUTE SHEET (RULE 26)

WO 2019/079249 PCT/US2018/056011

28/28 28/28

10° 10 TA TA

108# +/-SEM radiane Average 10 UTD 2/sr 2 9photons/sec/cm n E 7 10 10 1538 CAR 1538 CAR 19 19 +

1086 2200 10 2200 m m 971 971

105 2209 16P17 2209 16P 17

104 2219 16P13 10 2219 16P 13

10³ 10

22 10 6 14 21 28 35

Days PostTumor Im plant Days Post Tum or Im plant

Figure Figure 9 9

SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)